Essential respiratory medicine. Shanthi Paramothayan

Chapter 9. Lung cancer

Learning objectives

 To understand the epidemiology and risk factors for lung cancer

 To appreciate the importance of prevention and early detection

 To recognise the symptoms and signs of lung cancer

 To understand the investigations used to make a diagnosis of lung cancer

 To learn the classification of lung cancers

 To understand the radical and palliative management of lung cancer

 To appreciate the importance of a multidisciplinary approach in the management of lung cancer

 To understand the differential diagnoses and management of benign lung lesions

 To understand the differential diagnoses and management of solitary pulmonary nodules

Abbreviations

ALK anaplastic lymphoma kinase

APUD amine uptake and decarboxylation

AVM arterio-venous malformation

CEA carcinoembryonic antigen

CHART continuous hyper-fractionated accelerated radiotherapy

COPD chronic obstructive pulmonary disease

CT computed tomography

CXR chest X-ray

EBUS endobronchial ultrasound

EGF epidermal growth factor

EGFR epidermal growth factor receptor

EMLA echinoderm microtubule-associated protein-like 4

ENT ear, nose and throat

EUS endoscopic ultrasound

FDG 18F-Fluorodeoxy glucose

FEV1 forced expiratory volume in 1 second

FNA fine-needle aspiration

FVC forced vital capacity

Gy Grey is a derived

SI unit for ionising radiation

HPOA hypertrophic pulmonary osteoarthropy

LCNS lung cancer nurse specialist

MDT multidisciplinary team

MRI magnetic resonance imaging

NICE National Institute of Health and Care Excellence

NSCLC non-small cell lung cancer

PD-L1 programmed death ligand 1

PD-L1R programmed death ligand 1 receptor

PET-CT positron emission tomography with computed tomography

PORT post-operative radiation therapy

PSA prostate specific antigen

PTH parathyroid hormone

RCT randomised controlled trial

SABR stereotactic ablative radiotherapy

SCLC small cell lung cancer

SIADH syndrome of inappropriate anti-diuretic hormone

SPN solitary pulmonary nodule

SUV standardised uptake value

SVCO superior vena cava obstruction

TBNA transbronchial needle aspiration

TLCO diffusion capacity/transfer factor for CO

TWR two-week rule

UK United Kingdom

VATS video-assisted thoracoscopic surgery

VEGF vascular endothelial growth factor

WHO World Health Organisation

Introduction

The majority (95%) of primary lung cancers are bronchogenic carcinomas which arise from the epithelial cells of the bronchial mucosa. These can be subdivided into non-small cell lung cancer (NSCLC), which arises from the epithelial and glandular cells, and small cell lung cancer (SCLC), which arises from the neuroendocrine cells. Adenocarcinoma in situ, previously known as bronchoalveolar cell carcinoma (5%), arises from the alveolar cells. Mesothelioma, a malignant tumour of the pleura, is discussed in Chapter 12. Metastases to the lungs from other primary tumours, such as breast, colon, prostate, kidneys, ovary, and thyroid can also occur. In this chapter we will discuss primary lung tumours.

Lung cancer is the commonest fatal malignancy for both men and women in the UK and the third commonest cause of death in the UK. Worldwide, it accounts for one million deaths each year. Lung cancer has a poor prognosis because many types are rapidly growing, aggressive, and have usually metastasized at the time of presentation. In addition, lung cancer often presents late because many of the symptoms, such as cough and breathlessness, are non-specific and common in smokers. There is no screening programme for lung cancer in the UK. Current studies are evaluating whether screening is feasible, cost-effective, and likely to reduce mortality.

Epidemiology of lung cancer

 Incidence: 40 000/year in UK.

 Mortality: 34 000 deaths/year in UK.

 Male: Female ratio is 1.5 : 1, largely reflecting previous smoking habits in men and women (Figure 9.1).

 The prevalence of lung cancer in women is still increasing as there is a 30-year lag between smoking and developing lung cancer (Figure 9.2). Lung cancer has overtaken breast cancer as the leading cause of cancer deaths in women.

Figure 9.1 Lung cancer incidence and smoking trends for adults by sex, 1948-2010 in Great Britain, from Cancer Research UK.

Figure 9.2 Number of deaths and age-specific mortality rates for lung cancer in UK, 2007, from Cancer Research UK.

Figure 9.3 Survival in lung cancer according to stage at diagnosis. Source: from Staging at http://Cancer.org.

 There is a higher prevalence of lung cancer in the North of England and Scotland compared to the South of England reflecting the higher prevalence of smoking in those areas. Lung cancer is also commoner in the lower socio-economic groups: this may be due to smoking habits as well as poor nutrition.

 Survival: the overall 1-year survival for lung cancer is still only 30% in men and 35% in women with a 5-year survival of only 9.5% (Figure 9.3). There has been no convincing reduction in mortality despite some advances in diagnosis and treatment and the introduction of guidelines, pathways, and multidisciplinary working. This highlights the importance of prevention and early diagnosis.

Aetiology of lung cancer

Several factors are implicated in the development of lung cancer. These are listed in Box 9.1.

Some 90% of lung cancers are related to smoking, which is the main risk factor. Before smoking became popular in the twentieth century, lung cancer was rare. The probability of developing lung cancer correlates to the number and duration of cigarettes smoked, quantified as the number of pack years. The earlier the onset of smoking, the higher the risk of developing lung cancer, as there is a 30-year latent period.

A smoker of 20/day has 20x the risk of dying from lung cancer compared to a non-smoker.

Box 9.1 Aetiology of lung cancer.

 Cigarette smoking (active)

 Cigarette smoking (passive)

 Asbestos exposure

 Ionising radiation (radon gas): background radiation from the ground and rocks

 Polycyclic aromatic hydrocarbons

 Arsenic

 Genetic predisposition (family history): variation in ability to metabolise carcinogens

 Idiopathic pulmonary fibrosis

 Scar carcinoma: tumours can arise from areas of chronic fibrosis

____

The risk of developing lung cancer is halved every 5 years after smoking cessation but remains higher than for a non-smoker. The prevalence of smoking is slowly reducing in the UK, with 17.7% of men smoking on average 12 cigarettes daily and 15.8% women smoking approximately 11 cigarettes every day. However, rates of smoking and lung cancer are increasing in China, India, and other developing countries.

In the past decade, evidence has accumulated that passive smoking, caused by exposure to the cigarette smoke from others, increases the risk of lung cancer 1.5 x. This evidence has resulted in a ban in smoking in public places in the UK. Children are particularly vulnerable to the effects of smoking, especially in places with little ventilation, such as cars. It is likely that there will be further legislation to protect children.

Chapter 15 discusses the carcinogenic properties of cigarette smoke and the seminal studies by Hill and Doll establishing the link between lung cancer and smoking. In Chapter 3 the NICE guidelines for smoking cessation are discussed.

Asbestos exposure is a risk factor for developing lung cancer. Asbestos exposure and smoking act synergistically and increase the risk of lung cancer 100 times compared to a non-smoker. There is a latent period of 30-40 years from asbestos exposure to developing lung cancer. Asbestos exposure is also a risk factor for mesothelioma, a malignant tumour of the pleura, which is discussed in Chapter 10.

Pathophysiology of lung cancer

Damage to the bronchial mucosa by carcinogens causes squamous metaplasia which can progress to dysplasia, often in many separate areas. Some dysplastic cells then progress to become malignant. Areas of dysplasia can be visualised at bronchoscopy using fluoroscopy, but this is still largely a research tool.

The cancer initially invades local tissues, spreading to the parenchyma, pleura, pericardium, oesophagus, ribs, and muscle. This can result in cough, pain, breathlessness, dysphagia and pleural and pericardial effusions. Invasion of local nerves can cause vocal cord palsy (left recurrent laryngeal nerve), raised hemidiaphragm (phrenic nerve), and brachial plexus symptoms. The tumour can also spread to lymph nodes via the lymphatics and metastases to distant sites occurs haematogenously.

Clinical presentation of lung cancer

Lung cancer is a common condition, so all healthcare professionals should be alert to the possibility that patients with risk factors for lung cancer or a family history of malignancy, and who present with certain symptoms, may have lung cancer. Lung cancer can present with local or systemic symptoms, some of which are non-specific. As most patients with lung cancer are smokers and likely to have chronic obstructive pulmonary disease (COPD), many of the symptoms, such as cough (which is the commonest symptom of lung cancer) and worsening breathlessness may be overlooked by the patient and the doctor (Box 9.2). A detailed clinical history and thorough examination should be conducted. Basic investigations, such as a chest X-ray, should be conducted without delay and the patient referred to a specialist via the Two-Week Rule Pathway if there is any concern. Some 15% of lung cancers are found incidentally in patients who have had a chest X-ray (CXR) or computed tomography of the thorax (CT thorax) for other reasons, for example, during pre-assessment for surgery.

Box 9.2 Symptoms of lung cancer.

Respiratory symptoms

 Cough, persistent and longer than 3 weeks’ duration in 80% of cases

 Breathlessness, progressively worsening in 60% of cases

 Chest pain (from local invasion) in 50% of cases

 Haemoptysis in 30% of cases

 Monophonic wheeze

 Stridor

 Shoulder pain secondary to Pancoast’s tumour with invasion of the brachial plexus: this can result in weakness of the small muscles of the hand

 Hoarse voice suggests vocal cord palsy secondary to recurrent laryngeal nerve involvement

 Raised hemidiaphragm secondary to phrenic nerve palsy

 Superior vena cava obstruction (SVCO) can occur in 20% and is commoner with SCLC.

 Cervical or supraclavicular lymphadenopathy

Systemic symptoms

 Weight loss

 Lethargy

 Pain suggestive of metastases to other organs, for example, bone pain

 Neurological symptoms secondary to brain metastases

 Spinal cord compression

 Paraneoplastic symptoms result from the secretion of hormones or cytokines by the tumour. Lambert-Eaton myasthenic syndrome is associated with SCLC and results from autoantibodies to the presynaptic membrane

 Peripheral neuropathy

 Dermatomyositis

 Thrombophlebitis migrans

 Cerebellar degeneration

____

Clinical signs of lung cancer

Patients with early, asymptomatic lung cancer may not have any abnormal signs and clinical examination will be normal. Box 9.3 details some possible signs in patients with lung cancer.

Ectopic secretion of hormones in lung cancer

Small cell lung cancers, which originate from the Kutchinsky neuroendocrine cells of the amine uptake and decarboxylation (APUD) system, can secrete ectopic hormones, so patients with hyponatraemia or hypercalcaemia may have an underlying malignancy.

Box 9.3 Clinical signs of lung cancer.

 Cachexia

 Clubbing in 20% with NSCLC (Figure 9.4)

 Hypertrophic pulmonary osteopathy (HPOA) is commoner with adenocarcinoma and regresses with treatment of the primary cancer (Figure 9.5)

 Hoarse voice or bovine cough secondary to invasion of the left recurrent laryngeal nerve by tumour as it passes around the aortic arch to the superior mediastinum

 Tachypnoea

 Horner’s syndrome (meiosis, ptosis, enophthalmos, and anhydrosis) from invasion of the lower cervical sympathetic ganglion (Figure 9.6)

 Cervical lymphadenopathy

 Tracheal deviation (secondary to upper lobe collapse)

 Superior vena cava obstruction (SVCO).

 Clinical signs of lobar collapse (Figure 9.8)

 Clinical signs of pleural effusion

 Pathological fracture of bone

 Unexplained pulmonary emboli

 Unexplained hyponatraemia

 Unexplained hypercalcaemia

____

Ectopic secretion of anti-diuretic hormone (ADH) can occur in 15% of patients with SCLC resulting in hyponatraemia (serum sodium <139mmol/L). The patient can present with confusion and weakness. To make a diagnosis of syndrome of inappropriate ADH (SIADH) the serum osmolality must be <280 mosmol l-1 and the urine osmolality >500 mosmol l-1. Hyponatraemia due to SIADH can be managed by fluid restriction (1—1.5 l). If this fails, then pharmacological agents, such as demeclocycline, a vasopressin inhibitor or tolvaptan, a selective V2 receptor antagonist can be used.

Figure 9.4 Photograph showing clubbing of finger nails. Source: ABC of COPD, 3rd Edition, Figure 3.3.

Figure 9.5 X ray showing hypertrophic pulmonary osteoarthropathy (HPOA).

Figure 9.6 Photograph showing Horner’s syndrome. Source: Medical Photography, Epsom and St. Helier NHS Trust.

Figure 9.7 CXR showing a right-sided lung mass suspicious for lung cancer.

Hypercalcaemia (serum corrected calcium >2.8mmol/L) in lung cancer can be due to the secretion of parathyroid hormone-related (PTH-related) peptide by squamous cell carcinoma which binds to the PTH receptors and increases bone and tubular resorption and decreases bone formation. Hypercalcaemia can also occur when there are bone metastases. Hypercalcaemia secondary to malignancy responds well to i ntravenous fluids, intravenous diuretics, steroids (prednisolone or dexamathasone), and intravenous bisphosphonate, such as pamidronate.

Figure 9.8 CXR showing lobar (left upper lobe) collapse.

Figure 9.9 CXR showing a cavitating solitary pulmonary nodule.

Ectopic ACTH secretion is rare (2—5% with SCLC), but presents with raised cortisol and Cushing’s syndrome.

Management of superior vena cava obstruction (SVCO)

Patients with SVCO present with headaches, distended, engorged, pulseless neck veins, collateral veins on the chest and arms, and facial oedema. The CXR may show a mass on the right side of the thorax and a widened mediastinum. The diagnosis can be confirmed with a contrast CT thorax which can identify the anatomical structures and collateral circulation. Invasive contrast venography and Doppler scanning may be helpful in assessing the extent of the obstruction. Severe SVCO can present as an emergency and must be discussed with the respiratory and radiology consultants. Management depends on the patient and the imaging, but includes commencing dexamethasone (up to 8 mg twice a day), after tissue biopsy if possible. Insertion of a metallic stent by an interventional radiologist can be considered in an emergency, and anticoagulation must be considered if there is thrombus present. Radiotherapy for NSCLC and chemotherapy for SCLC can reduce the obstruction but may take weeks to be effective.

Management of a patient suspected of having a lung malignancy

Lung cancer has a poor prognosis because patients often present late with evidence of local or distant metastases. This may be because neither the patient nor the doctor is alert to the common symptoms of lung cancer, which are often non-specific. Currently there is no screening programme to detect lung cancer early. Other factors resulting in low survival rates for lung cancer in the UK include poor surgical rates of only 15% compared to at least 20% in the USA and in Europe. Patients with lung cancer also have significant co-morbidities which often preclude radical treatment.

To improve early referral, diagnosis, and treatment, patients with symptoms or signs suggestive of lung cancer must be referred as a two-week rule (TWR) to the respiratory team. The patient must be seen by a consultant respiratory physician within

14 days of referral, have all investigations completed within 28 days of referral, be discussed at the lung cancer multidisciplinary team (MDT) meeting and have treatment within 62 days of the original referral. These timeframes are likely to reduce in the next few years.

Clinical assessment of patient with suspected lung cancer

Patients should have a detailed history and examination (see Box 9.2, Box 9.3). In addition, the World Health Organisation (WHO) performance status, oxygen saturation, and spirometry must be noted (Box 9.4).

Investigations for patients suspected of having lung cancer

Blood tests should include full blood count to exclude anaemia and infection, urea and electrolytes, liver function test, clotting, corrected calcium and plasma and urine osmolalities if there is hyponatraemia.

Radiological investigations includes a plain chest X-ray followed by a contrast staging CT scan of thorax and abdomen. Box 9.5 details chest X-ray changes that need to be investigated further. Rarely, with central tumours or with small tumours, the chest X-ray may appear normal. If the patient has unexplained symptoms or signs, which includes haemoptysis, a staging CT scan is indicated even if the chest X-ray appears normal.

A staging CT scan of thorax and abdomen with contrast will show the primary tumour, lymph node enlargement within the thorax, local lung metastases and distant metastases to liver, adrenal glands and bone (Figure 9.12).

A CT-PET scan is required for accurate staging and is essential if radical treatment is being considered. A CT-PET scan is done in a specialist centre and can ‘up’ or ‘down’ stage the CT staging. A CT- PET has a sensitivity of 95% and a specificity of 83% for lung cancer.

Box 9.4 WHO performance status.

1. able to carry out normal activity

2. symptomatic but ambulatory and able to carry out light work

3. in bed 50% of the day, unable to work but capable of self-care

4. in bed >50% of the day, limited self-care

5. bedridden, unable to self-care

____

Box 9.5 CXR appearances of concern.

 Mass (Figure 9.7)

 Lobar collapse (Figure 9.8)

 Solitary pulmonary nodule (SPN) (Figure 9.9)

 Lymphadenopathy

 Pleural effusion

 Unilateral raised hemidiaphragm (Figure 9.10)

 Persistent consolidation

 Lymphangitis carcinomatosis: there is infiltration of the pulmonary lymphatics by tumour (Figure 9.11). The appearances can resemble pulmonary oedema

____

Figure 9.10 CXR showing elevation of the right hemidiaphragm.

A CT-PET is poor at detecting slow-growing tumours, such as adenocarcinoma in situ and carcinoid tumours, and poor at detecting brain metasta- ses. False positive CT-PET scans can also be found with infective and inflammatory processes. The standardised uptake value (SUV max) is used to calculate the FDG uptake (Figure 9.13). An SUV max <2.5 suggests a benign lesion (Figure 9.14).

A bone scan may be indicated if the patient has bone pain or hypercalcaemia to see if there are bony metastases, although this can also be detected with a CT-PET scan.

Figure 9.11 CXR showing lymphangitis carcinomatosis.

Figure 9.12 CT thorax showing a suspicious, spiculate mass in the right upper lobe.

Figure 9.13 PET scan showing an FDG-avid lesion in the right upper lobe suspicious of lung cancer.

Figure 9.14 CT and PET scans showing a non-FDG-avid nodule in the left lung.

An MRI scan of the thorax can determine if the tumour involves the chest wall and may be required if resection of the chest wall is being considered. It is also useful for assessing the extent of the disease in superior sulcus tumours. An urgent MRI scan is indicated for spinal cord compression. An MRI brain may be required if there is indication of an operable brain metastasis.

A CT brain scan is required if the patient has neurological symptoms or signs suggestive of brain metastases. It is also done routinely in patients who are being considered for radical treatment.

Histological diagnosis

The NICE guidelines (2011) stipulate that histological diagnosis should be obtained in at least 85% of patients presenting with lung cancer. However, an invasive procedure carries a risk of morbidity and even mortality. The patient must be fully informed of the potential risks and benefits of any invasive procedures and must be prepared to accept these risks.

The investigation that gives the most information about the diagnosis and staging with the least risk to the patient should be chosen. For example, if there are enlarged lymph nodes of more than 10 mm maximum short axis on CT, then these should be sampled by endobronchial ultrasound (EBUS)-guided biopsy or transbronchial needle aspiration (TBNA). Neck ultrasound and sampling of visible lymph nodes is also advised. Several samples may need to be taken to get sufficient tissue to identify the mutational status of the tumour which can guide treatment. While it is important to take adequate samples, the patient should not be put at any risk. Histology obtained from a biopsy is preferred to cells obtained from brushings and washing alone, although often, as the case with a pleural effusion, a cytological diagnosis may be sufficient.

Sputum cytology can be helpful in 40% of cases and more likely to be diagnostic with central tumours. This may be the only way to get cytological confirmation if the patient is too unfit for an invasive procedure such as a bronchoscopy.

A flexible fibre-optic bronchoscopy is often the first investigation used to obtain tissue if the tumour is endobronchial and central. The tumour can be directly visualised and the distance of the tumour from the carina and the extent of obstruction of the bronchus can be noted. Bronchoscopy can also identify vocal cord palsy.

Biopsies, brushings and washings (bronchoalveolar lavage) can be taken directly from the tumour site through the bronchoscope for histological diagnosis. Sometimes, although no definite endobronchial lesions are seen, mucosal abnormalities may be visible which can be biopsied. The centre of a large tumour mass is often necrotic, so samples may not be diagnostic, even when large pieces of tissue are obtained. Other limitations to obtaining an adequate sample include poor patient tolerance of the procedure and vascular tumours that bleed easily. A rigid bronchoscopy, which is done under general anaesthetic, gives the operator more control, and may increase the diagnostic yield with difficult cases and when the tumour is near the carina.

If the tumour is peripheral, then a CT-guided fine needle aspiration (FNA) conducted by the radiologist is diagnostic in 90—95% of cases when the lesion is >2 cm. It is not possible to undertake an FNA on a lesion <1 cm (Figure 9.15). Patients referred for this must have reasonable spirometry, normal oxygen saturation, be able to hold their breath and able to lie down flat. CT-guided FNA is usually contraindicated in patients with an FEV1 of less than 1 L and with severe emphysematous lung disease on CT scan as their risk of pneumothorax is high and they will not be able to safely tolerate it. The overall pneumothorax risk of a CT-guided FNA is 20%.

Figure 9.15 CT-guided FNA of lung mass showing needle in the lung mass.

The other risk of lung biopsy is bleeding, with 8% experiencing haemoptysis post-procedure. If the patient is on an anticoagulant, then this must be stopped several days prior to the procedure and clotting checked. The patient may need to be treated with low molecular weight heparin in the interim if necessary. Patients on aspirin should be informed not to take aspirin on the day of the procedure.

Sampling of enlarged, PET positive lymph nodes will ensure accurate staging which can determine whether the patient should receive radical or palliative treatment. Transbronchial needle aspiration (TBNA), endobronchial ultrasound (EBUS), and endoscopic ultrasound (EUS) can be used to biopsy paratracheal and peribronchial nodes. A mediastinoscopy can be done under general anaesthetic by a thoracic surgeon to sample mediastinal lymph nodes.

Cytology obtained by pleural aspiration of a pleural effusion can be diagnostic of lung cancer, but histology is preferable as tissue is required for molecular testing. A video-assisted thoracoscopic (VATS) pleural biopsy done under general anaesthetic can be diagnostic when there is pleural involvement. Histological diagnosis of lung cancer can also be made by taking a biopsy from an extra-thoracic site, such as a cervical or supraclavicular lymph node, the liver, adrenal, skin or bone (Figure 9.16). This may be necessary when CT-guided FNA of the primary lung lesion is not possible.

Figure 9.16 Histology of adenocarcinoma from a CT-guided biopsy of lung mass.

Figure 9.17 Histology of squamous cell carcinoma from a CT-guided biopsy of lung mass.

Figure 9.18 Histology of small cell carcinoma from an endobronchial biopsy.

While every attempt should be made to obtain a histological diagnosis, this is often limited by the patient’s poor performance status (WHO performance status 3 or 4) and co-morbidities (Figure 9.17, Figure 9.18). The decision not to pursue a histological diagnosis should be made at the lung cancer MDT after discussion with the patient and family. Pursuing a histological diagnosis may not be recommended in frail patients with a poor performance status, and in patients with extensive disease who are only suitable for palliation. Some patients may choose not to pursue further investigations for a variety of reasons and their wishes must be respected, so long as all the information has been given in a clear way. Good and empathetic communication is essential when dealing with patients with lung cancer.

Other investigations required in a patient with suspected lung cancer includes spirometry to assess the patient’s fitness for a procedure, such as a CT-guided biopsy. If this suggests an airways obstruction, then the patient should be given optimal treatment to improve symptoms. A full lung function with transfer factor is required when planning radical treatment, such as surgery or r adiotherapy. An ECG and echocardiogram may be necessary prior to radical treatment if the patient has a cardiac history.

Classification of lung cancer

Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancers. Small cell lung cancer (SCLC), previously called oat-cell cancer, is more aggressive and accounts for 20% of lung cancers.

Histological diagnosis is made from the morphological characteristics of the cells and the immunophenotyping. The biopsy is first processed and assessed by routine haematoxylin and eosin (H + E) stained sections. In most cases, a reliable diagnosis of NSCLC or SCLC can be made, although when the tumour is very poorly differentiated, this can be difficult. With advances in chemotherapy and immunotherapy, it is no longer acceptable to classify tumours simply as NSCLC.

Immunocytochemistry is required to classify NSCLC as squamous cell carcinoma or adenocarcinoma. Immunocytochemistry is a technique in which antigens in the tumour cells are bound to antibodies with attached chemical markers that allow them to be visualised in tissue sections. Many antibodies are available and their affinity to the different tumour markers has often been found empirically. The sensitivity and specificity are therefore variable, and it is normal to use a panel of antibodies. It can be difficult to differentiate between a primary lung adenocarcinoma and metastases from prostate, breast, and colon. Other markers may be helpful in differentiating between lung and metastases from other organs. By using these methods, over 90% of tumours can be classified accurately.

Tissue should be conserved for molecular mutation testing, such as for Epidermal Growth Factor Receptor (EGFR,) programmed death ligand 1 and its receptor (PD-L1), and anaplastic lymphoma kinase (ALK). NICE guidelines recommend that the majority of NSCLC should have testing for EGFR. EGFR inhibitors are discussed later in this chapter.

There has been a change in the type of lung cancer over the last decade, with a decrease in squamous cell carcinoma and an increase in adenocarcinoma. This may be due to an increase in the low-yield brands of cigarettes with filters which result in more peripheral deposition of carcinogens.

Staging of NSCLC

The TNM classification is used to stage NSCLC (Tables 9.1 and 9.2). The TNM classification was revised by the International Staging Committee of the International Association for the study of Lung Cancer. Data was collected on 68 463 patients with NSCLC and 13 032 patients with SCLC between 1990 and 2000. The modifications were recommended because of differences in survival and prognosis. Although it is not used in routine practice, staging that includes size of tumour, the histological type, late recurrence risk, and the age of the patient is more accurate. Accurate staging guides management and enables a more accurate prognosis to be made. Table 9.3 details the overall survival of patients with NSCLC according to the stage of the disease.

Staging of SCLC

The majority of SCLC present with evidence of metastases. If the disease is confined to the thorax, then it is staged as “limited”, and if there is evidence of spreading outside the thorax, then it is staged as “extensive”.

Management of lung cancer

Treatment decisions are made by the lung cancer multidisciplinary team (MDT) after consideration of the histological cell type (including immunocytochemistry), radiological stage, performance s tatus of patient, lung function, co-morbidities, and the wishes of the patient.

The key decision is whether the patient is suitable for radical, potentially curative treatment: surgery or radiotherapy. This can be followed by adjuvant treatment, either chemotherapy, radiotherapy, or both.

If the cancer is too advanced for radical treatment or the patient is unfit for radical treatment, then palliative options, which include chemotherapy and radiotherapy, can be considered. Palliation also includes procedures such as insertion of an endobronchial stent and draining of a pleural effusion with pleurodesis to relieve breathlessness. When patients have advanced disease and a poor performance status, then symptom control may be the best option. In the next section the various treatment options are discussed.

Surgery

The aim of surgery in lung cancer is to remove the tumour completely and it offers the only real chance of a cure. The latest figures from the National Lung Cancer Audit show that only 15% of patients with lung cancer in the UK have surgical resection. Although this is an improvement from previous years, it is poor compared to figures in Europe and USA, where over 20% of patients had surgical resection.

This low resection rate may be because patients with lung cancer present late with locally advanced or widely disseminated disease. However, there is evidence that not every patient who is suitable for surgery is referred for a surgical opinion.

Table 9.1 Eighth edition of TNM classification of NSCLC.

T = Size of tumour in CM.

TX: primary tumour cannot be assessed, or tumour cells in sputum or bronchial cells, but not visualised at bronchoscopy.

T0: No evidence of primary tumour.

Tis: Carcinoma in situ.

T1: Tumour <3 cm in greater dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (not in main bronchus).

T1mi: minimally invasive adenocarcinoma.

T1a: tumour <1 cm or less in greatest dimension.

T1b: tumour >1 cm and < 2 cm in greatest dimension.

T1c: tumour >2 cm but <3 cm in greatest dimension.

T2: tumour >3 cm but <5 cm or with any of the following features: involves main bronchus regardless of distance to the carina, but not involving the carina, invades visceral pleura, associated with atelectasis or obstructive pneumonia that extends to the hilar region either involving part or the entire lung.

T2a: tumour >3 cm but <4 cm in greatest dimension.

T2b: tumour >4 cm but <5 cm in greatest dimension.

T3: tumour >5 cm but <7 cm in greatest dimension or one that directly invades any of the following: parietal pleura, chest wall (including superior sulcus tumours), phrenic nerve, parietal pericardium: or separate tumour nodule (s) in the same lobe as the primary.

T4: tumour >7 cm or of any size that invades any of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina; separate tumour nodule(s) in a different ipsilateral lobe to that of the primary.

N = regional lymph node involvement

NX: Regional lymph nodes cannot be assessed.

N0: No regional evidence of 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).

M = distant metastasis

M0: No evidence of distant metastasis.

M1: Distant metastasis.

M1a: Separate tumour nodule(s) in a contralateral lobe; tumour with pleural or pericardial nodules or malignant pleural or pericardial effusion.

M1b: Single extrathoracic metastasis in a single organ.

M1c: Multiple extrathoracic metastases in a single, or multiple organs.

_____

Table 9.2 Staging using the TNM classification for NSCLC eighth edition.

Stage

T

N

M

Occult

Tx

N0

M0

0

Tis

N0

M0

IA

T1

N0

M0

IA1

T1mi

N0

M0

 

T1a

N0

M0

IA2

T1b

N0

M0

IA3

T1c

N0

M0

IB

T2a

N0

M0

IIA

T2b

N0

M0

IIB

T1a-c,

T2a, b

N1

M0

 

IIIA T3

N0

M0

IIB

T1a-c,

T2a, b

N3

M0

 

T3, T4

N2

M0

IIIC

T3, T4

N3

M0

IV

Any T

Any N

M1

IVA

Any T

Any N

M1a,

     

M1b

IVB

Any T

Any N

M1c

Table 9.3 Overall 5-year survival for NSCLC.

Stage

5-year survival rate (%)

IA

49

IB

45

IIA

30

IIB

31

IIIA

14

IIIB

5

IV

1

Source: http://www.cancer.org/cancer.

Of those undergoing resection, only 30% will be alive in 5 years. The prognosis depends on the final pathological stage of the cancer.

Surgery with curative intent should be considered in patients who are medically fit (WHO performance status 0 or 1), who have a reasonable lung function, and who have no significant co-morbidities. This includes NSCLC Stages la to Stage Illa (up to T3N1M0).

Surgery includes the removal of a lobe (lobectomy) or the entire lung (pneumonectomy). A pneumonectomy would be indicated if hilar nodes are found to be involved. The aim is to ensure that the resection margins are macroscopically free of tumour. The local lymph nodes are removed at surgery for pathological staging.

If the patient’s lung function and performance status are poor, then a wedge resection or segmentectomy can be considered for peripheral tumours. The tumour, with a small amount of surrounding lung tissue, is removed. Where appropriate, bron- choangioplastic or sleeve resections may sometimes be possible to preserve the lung function. The mortality for this procedure is 1—3.5% and the tumour recurrence rate is about 23%.

Those who have had a lobectomy have better survival rates than segmentectomy for tumours >3 cm. Local recurrence after lobectomy is less compared to segmentectomy regardless of the size of the tumour. A Cochrane meta-analysis of 11 RCTs showed that 4-year survival was increased in patients with Stage I, II and IIIA NSCLC who underwent lobectomy and complete mediastinal lymph node dissection compared to those who had complete resection and lymph node sampling. There were differences in operative mortality between the groups, with more complications in the lymph node dissection group.

Surgery is occasionally considered for selected patients with Stage IIIA NSCLC (T4N0M0, T4N1M0, T1-3N2M0) as part of radical multimodality management with neoadjuvant chemotherapy and/or radiotherapy which may reduce the tumour size. Restaging may confirm operability. Stage IIIB NSCLC and Stage IV NSCLC are considered inoperable.

Neurosurgical resection can be considered for a solitary brain metastasis. The staging described in the section refers to the TNM classification version 7.

Essential investigations prior to surgery

A staging CT scan with contrast of the thorax and upper abdomen, which is an essential investigation for all patients with lung cancer, will demonstrate tumour anatomy, location, and size, with an accurate measurement of the T-stage. CT also demonstrates abnormal enlargement of loco-regional lymph nodes based on the size in the short axis and gives information about other diseases, such as emphysema. A PET-CT will clarify lymph node involvement and detect occult metastases and is essential prior to surgery.

Fitness for surgery

The average mortality risk for lobectomy in the UK is 2—3%. In assessing fitness for surgery, the operative mortality, the risk of peri-operative myocardial events and the risk of post-operative dyspnoea should be considered. Patients should also be counselled regarding commonly occurring complications associated with lung resection.

Although age is not an absolute contraindication, patients aged over 80 do have an increased morbidity and mortality. Patients over 80 who have a lobectomy have a 7% mortality compared to 2—3% in younger patients. Those over 80 undergoing a pneumonectomy have a 14% mortality compared to 5—6% in younger patients. Despite this, the increased resection rates seen in recent years have been most marked in the older age group, probably reflecting a longer life expectancy.

Lung function is used in the pre-operative assessment to estimate the risk of operative mortality and the impact of lung resection on quality of life, especially in relation to post-resection dyspnoea. Although often regarded as being very important in assessing patients for surgery, forced expiratory volume in 1 second (FEV1) has not been shown to be an independent predictive factor for perioperative death and best serves as a useful predictor of postoperative dyspnoea. Diffusion capacity (TLCO) is an important predictor of post-operative morbidity and should be performed in all patients regardless of spirometric values. A TLCO of greater than 40% predicted is required for surgery to be considered.

Although values of FEV1 > 1.5 L for a lobectomy and FEV1 > 2 L for a pneumonectomy were previously used in recommending surgery, surgical resection should still be offered to patients at moderate to high risk of post-operative dyspnoea and associated complications if it is felt that this is the better treatment option and the patient is willing to accept the higher risk.

Several other investigations can be useful for assessing the fitness of patients with moderate to high risk of post-operative dyspnoea and borderline lung function: ventilation and perfusion scintigraphy (VQ scan), quantitative CT or MRI, cardiopulmonary exercise testing and shuttle walk testing.

Patients should be informed that smoking increases the risk of pulmonary complications. They should be strongly advised to stop smoking, prescribed medication to aid smoking cessation, and referred to a smoking cessation clinic. Smoking cessation is discussed in Chapter 3.

Patients with co-morbidities will require appropriate investigations prior to referral for surgery. Cardiac problems are common, so patients may require an ECG, echocardiogram, and a cardiac opinion. Surgery should be avoided within 30 days of a myocardial infarction. Patients with coronary artery disease should have their medical treatment and secondary prophylaxis optimised as soon as possible.

It is essential to rule out metastases prior to referral for surgery. Although a CT-PET scan can detect most metastases, it is not good at detecting brain metastases, so a CT brain should be done.

Post-operative complications

Complications of lung resection can be divided into three categories. Pulmonary complications include atelectasis, pneumonia, empyema, prolonged air leak, basal collapse, hypoxaemia, and respiratory failure. Post-operative air leaks often occur from a breach in the visceral pleura, so drains are placed at the time of surgery to deal with this. In most cases, prolonged drainage is sufficient and rarely is re-operation necessary to seal the leak. Bronchopleural fistula is a serious complication after pneumonectomy, with a high morbidity and mortality. The bronchial stump dehisces, and the pneumonectomy space inevitably becomes infected. Early mobilisation and physiotherapy are vital to reduce some of these complications. Cardiovascular complications include arrhythmia and myocardial infarction. Other common complications include bleeding, wound infection, and chronic chest wall pain.

Table 9.4 Differences in 5-year survival rates with CT staging and pathological staging.

CT staging

5 year survival (%)

Pathological staging

5 year survival (%)

CNO without surgery

42

pN0

56

CNO with surgery

50

   

CN1 without surgery

29

pN1

38

CN1 with surgery

39

   

CN2 without surgery

18

pN2

22

CN2 with surgery

31

   

CN3 without surgery

7

pN3

6

CN3 with surgery

21

   

M1a (nodules in another ipsilateral lobe)

16

   

M1a (pleural metastases)

6

   

M1b (contralateral lung nodule

3

   

M1b (distant metastases)

1

   

Follow-up post-surgery

All patients who have had surgery for lung cancer should be discussed at the Lung MDT with the full surgical and pathological report where decisions regarding the need for adjuvant chemotherapy or radiotherapy can be made. Patients who have had surgery for lung cancer require careful and regular follow-up for 5 years, with regular CXR and CT thorax at 12 months. The patient should be advised to report any symptoms of concern.

If the resection margins are not clear or nodal disease is found at surgery, then radiotherapy can reduce the chance of local recurrence, although it does not improve survival. There is no evidence that patients with Stage IA NSCL who have clear resection margins benefit from adjuvant chemotherapy or radiotherapy, although a significant number will eventually develop local or distant metastases. For Stage IB disease, chemotherapy may offer survival benefits if the tumour is >4 cm. Chemotherapy may be effective in patients with Stage II and Stage IIIA NSCLC after surgery.

Post-operative radiation therapy (PORT) does not improve the outcome of patients with completely resected Stage I NSCLC.

Table 9.5 5-year survival after surgery for NSCLC.

Stage IA (T1N0M0): 70%

Stage IB (T2N0M0): 40%

Stage II (T1-2N1M0): 25%

____

Table 9.4 compares the differences in 5-year survival rates with CT and pathological staging. Table 9.5 describes the 5-year survival after surgery for NSCLC.

Radiotherapy

Radical radiotherapy

Radical radiotherapy with curative intent can be given either alone or as part of a multi-modal treatment approach with chemotherapy and/or surgery. Radical radiotherapy can be considered for patients with early stage NSCLC (Stages I, II, IIIA) who are not suitable for surgery due to co-morbidities or those who decline surgery. Squamous cell carcinomas are more radiosensitive than adenocarcinomas. One-year survival after radical radiotherapy is 60% for Stage IA and 32% for Stage IB NSCLC.

A sub-group of patients with small peripheral tumours are suitable for complex highly focused stereotactic ablative radiotherapy (SABR) which is associated with excellent local disease control. Radical radiotherapy is also the mainstay of treatment for patients with locally advanced inoperable disease, either as single modality treatment or combined with chemotherapy. This can be given either concomitantly or sequentially and is associated with improved outcomes. Patients need to have a good WHO performance status of 0—1 and have FEV1, FVC and TLCO>40% predicted. Stereotactic treatment could be considered in patients with worse lung function.

Modern radiotherapy planning and delivery techniques ensure adequate doses are delivered to the tumour with limited damage to the surrounding normal tissues. Standard radical fractionation schedules comprise of 60—66 Gy given in 30—34 daily fractions over 6—7 weeks. There is evidence to suggest that accelerating the course of treatment and completing it over a shorter time is associated with improved outcomes. This can be done either by increasing the number of fractions given per day (hyper-fractionation), for example, using the continuous hyper-fractionated accelerated radiotherapy (CHART) schedule, or by increasing the dose given per fraction (hypo-fractionation), for example, 55 Gy given in 20 daily fractions over 4 weeks.

Side effects of thoracic radiotherapy include breathlessness, cough, tiredness, nausea, skin reaction, and dysphagia. Post-radiation pulmonary fibrosis can also occur, causing breathlessness.

Palliative radiotherapy

Palliative radiotherapy can improve symptoms of pain and haemoptysis in patients with lung cancer. It can also be effective in treating bone and brain metastases. Radiotherapy can also relieve breathlessness secondary to lobar collapse caused by tumour obstruction.

Radiotherapy may be indicated as emergency treatment in patients with spinal cord compression who are not suitable for neurosurgical intervention. It can be considered for mediastinal compressive symptoms, such as SVCO, stridor, and dysphagia.

Palliative radiotherapy schedules include 36 Gy in 12 daily fractions, 20 Gy in 5 daily fractions and single fractions of 8—10 Gy, depending on treatment intent and the patient’s performance status. Endobronchial brachytherapy may also be considered for local disease control.

Chemotherapy

Chemotherapy forms part of the potential treatment modality for most patients diagnosed with lung cancer. It is rarely curative but is the only option for most patients with SCLC and in many patients with NSCLC. Most lung cancers are disseminated at presentation and chemotherapy offers systemic treatment. It can also be given as adjuvant treatment to increase survival after surgery. It is often given in combination with radiotherapy to increase treatment response and survival. Neo-adjuvant chemotherapy can be given to downstage a tumour in the hope that this will make it radically treatable. There is usually a good initial response to chemotherapy with a reduction in tumour size and an improvement in symptoms in 70% of patients. Patients who are unfit for radical treatment may benefit from palliative chemotherapy.

Assessing fitness for chemotherapy

The toxicity of chemotherapy needs to be considered when offering patients systemic treatment. Underlying coronary artery disease, renal impairment, tinnitus, and peripheral neuropathy are particularly relevant. The functional status of the patient should be assessed using either the WHO performance status or the Karnofsky scoring system. The potential benefits and side effects of treatment should be discussed with the patient.

Chemotherapy for NSCLC

NICE guidelines (2011) recommend that chemotherapy is considered for patients with Stage III and IV NSCLC with a performance status of 0 or 1. Treatment can prolong life by two months and increase one-year survival from 5% to 25%. There are many clinical trials recruiting patients who should be offered the chance to participate.

Combinations of drugs are given at intervals of four weeks, up to six cycles of treatment, with careful monitoring of clinical and radiological response. Third-generation drugs, which include docetaxel, gemcitabine, paclitaxel, vinorelbine, and pemetrexed are given together with platinum drugs, carboplatin, or cisplatin. It is not within the scope of this book to discuss the details of chemotherapy drugs.

Adjuvant chemotherapy can be given after radical treatment, either radiotherapy or surgery. It is given after surgery for Stage IB disease when the tumour is >4 cm and for Stage II and Stage III lung cancer. A platinum-agent or a third-generation drug except pemetrexed can be given.

Neo-adjuvant chemotherapy should be considered is patients who are not radically treatable. Chemotherapy could downstage the tumour, making it suitable either for radical radiotherapy or surgery.

Chemotherapy for SCLC

NICE guidelines recommend that patients with SCLC should be seen by a medical oncologist within a week of diagnosis. Surgery should be considered for patients with early-stage SCLC (T1-2aN0M0) with a good WHO performance status of 0 or 1. Patients with SCLC undergoing surgery will require adjuvant chemotherapy. Radiotherapy may also be an option for early stage SCLC.

Chemotherapy can improve survival from 3 months to 12 months in limited SCLC and from 6 weeks to 12 weeks in extensive SCLC. Drugs used to treat SCLC include Topisomerase 1 poison (Topotecan), Topisomerase 11 poison (Etoposide) and the platinum drugs, carboplatin and cisplatin.

Palliative chemotherapy

A combination of a third-generation drug and a platinum drug is given if the patient can tolerate it without toxicity and the renal function is reasonable. Combinations of drugs given at intervals of 3 weeks, up to a maximum of six cycles, can improve symptoms.

Side effects of chemotherapy

The side effects of chemotherapy include systemic symptoms, such as nausea, vomiting, and diarrhoea which can be managed with antiemetics and fluids. Bone marrow suppression a few days after chemotherapy can result in anaemia, neutropenia, and thrombocytopaenia. Neutropenic sepsis is a real concern and must be considered in all patients who present feeling unwell. Neutropenic sepsis should be managed according to the NICE guidelines. It includes careful clinical assessment, septic screen (blood culture, urine culture, and chest X- ray), barrier nursing, and immediate intravenous antibiotics, usually tazocin and gentamicin.

Box 9.6 Radiological assessment of treatment response.

 Disease progression: the development of new lesions or an increase in tumour measurement by at least 20%

 Partial response: at least a 30% decrease in tumour measurements

 Stable disease: up to a 19% increase or 29% decrease in tumour measurements

 Complete response: resolution of all previously visible tumour and tumour markers

____

Treatment response

Response to treatment is assessed according to an improvement in symptoms and radiological improvement. Radiological treatment response is classified as defined in Box 9.6.

Targeted molecular therapy

Cancer cells have been found to have an overexpression of certain receptors. The ability to target specific proteins has been a major development in the treatment of patients with incurable lung cancer. Inhibitors which target several receptors have been developed, tested in trials, and have a licence for use in patients.

Epithelial growth factor receptor (EGFR) has been found to be over-expressed in non-smokers with adenocarcinoma, particularly women. EGFR inhibitors, such as Geftinib (Iressa) and Erlotinib (Tarceva), are particularly active in patients whose tumours contain an EGFR-activating mutation. Erlotinib has also demonstrated efficacy in patients who have relapsed after first line chemotherapy.

Bevacizumab is a monoclonal antibody that binds vascular endothelial growth factor (VEGF)

and can be used in combination with chemotherapy. Crizotinib targets a constitutively active kinase formed by a chromosomal rearrangement between the EMLA (echinoderm microtubule-associated protein-like 4) and anaplastic lymphoma kinase (ALK) genes. Expression of programmed death ligand 1 protein on the surface of cancer cells increases the responsiveness to immunotherapy. Immunotherapies that target the programmed death ligand 1 (PD-L1) and its receptor (PD-L1R) have been shown to increase survival in a subgroup of patients with advanced NSCLC.

The systemic treatment of lung cancer is rapidly changing. There are new and exciting developments in immunotherapy. It is beyond the scope of this book to discuss these in detail.

Palliative treatment

Palliative treatment, which focuses on the relief of symptoms, is the only option for most patients with SCLC and many with NSCLC. Patients should be referred to the palliative care team of doctors and nurses who specialise in symptom control. Patients can be seen in the hospital, in the hospice, or in the community. Symptoms that can be managed effectively include pain, breathlessness, nausea, constipation, anxiety, and insomnia.

The palliative care team can also offer psychological and emotional support to the patient and their family. They can refer the patient to the occupational therapist, physiotherapist, and social services. They can offer support and discussion about where the patient wishes to spend the last days of their life and where they wish to die, whether in a hospital, hospice or at home with appropriate support (hospice at home). Decisions about end-of-life care and the ceiling of treatment should be fully discussed with the patient and his/her family and should also be shared with all healthcare practitioners. Documentation and entry into a register, such as Co-ordinate My Care, will enable this to happen.

Palliative procedures

An endobronchial stent, inserted through a rigid bronchoscope, can aerate a part of the lung that has collapsed secondary to endobronchial obstruction caused by the tumour. This is most successful if the narrowing caused by the tumour is in one specific area. The patient will need to be fit enough for a general anaesthetic and have a prognosis of at least a few months. An endobronchial laser through a rigid bronchoscope can also open-up a bronchus narrowed by tumour. Endobronchial radiotherapy can cause shrinkage of an endobronchial tumour and reduce haemoptysis.

A malignant pleural effusion can be drained, followed by either a medical or surgical pleurodesis. A surgical pleurodesis using talc is generally preferable and more successful but requires that the patient is fit enough for general anaesthetic. A pleurax catheter can also be inserted for a recurring malignant pleural effusion. This may be an option in a patient who is still undergoing chemotherapy. The management of a malignant pleural effusion is discussed fully in Chapter 10.

Communicating the diagnosis of lung cancer

It can be difficult to inform a patient and his/her family the diagnosis of lung cancer, particularly if the disease is advanced and there is no curative treatment. Patients will be distressed and will go through the various stages of grief. They may become angry, and may blame themselves or the healthcare professionals if there has been any delay in obtaining the diagnosis. They may ask many questions, some of which can be difficult to answer. Most commonly, patients ask about their prognosis. This can be difficult to determine so should be discussed by a senior doctor who has all the information to hand. All patients with lung cancer should be discussed in the lung cancer MDT. All conversations should be recorded in the notes so that other healthcare professionals reading them are aware of what has been discussed and the completed proforma should be sent to the GP

The lung multidisciplinary meeting

All patients with lung cancer must be discussed at the multidisciplinary meeting in a timely way. The MDT comprises of a respiratory physician, radiologist, histopathologist, medical oncologist, clinical oncologist, thoracic surgeon, palliative care consultant, and a lung cancer nurse specialist (LCNS). The LCNS should ideally be present when the patient receives the diagnosis of lung cancer and at discussions regarding management. The LCNS will offer additional information, for example, about benefits, offer support to the patient and family, and liaise with other members of the team. The lung MDT co-ordinator prepares the list and notes for the MDT and enters the data into a National Database.

The documentation must include information about the staging of the cancer, the WHO performance status of the patient (see Box 9.4) and the management plan which must be communicated to the patient, the GP, and other relevant people, such as the palliative care team.

Tracheal and laryngeal tumours

Tracheal and laryngeal tumours have a similar aetiology to primary lung cancers, with smoking being the main risk factor. Tracheal tumours may present with breathlessness, wheeze, and stridor. A CXR may appear misleadingly normal. An urgent CT scan of the upper thorax and neck may show the tumour. Bronchoscopy and biopsy should be carried out with caution as there is a possibility of causing complete obstruction of the airway if the tumour is large or if there is bleeding post-biopsy. It may be safer to carry out a rigid bronchoscopy under general anaesthetic with ENT support if necessary. Carcinoma of the larynx usually presents with a hoarse voice secondary to vocal cord paralysis. The diagnosis is made by bronchoscopy or nasendoscopy and is managed by the ENT surgeons.

Benign lung masses and solitary pulmonary nodules (SPN)

With improvements in CT scanning techniques and the increased frequency of scanning, there has been an increase in the detection of lung nodules and masses. A lesion <3 cm is considered a solitary pulmonary nodule (SPN) and one >3 cm as a pulmonary mass. It must be assumed that any mass or nodule in the lung is malignant unless radiological features or a biopsy prove otherwise. If a patient is referred with an abnormal CXR, it is useful, if possible, to look at previous imaging to see if this is a new nodule or if there has been any changes in the size or shape of the nodule. Benign pulmonary masses or nodules, which are often congenital, will appear stable in appearance on serial imaging.

Table 9.6 Features of malignant and benign lung lesions.

Malignant

Benign

Older age

Younger age (<40 years)

Smoker

Non-smoker

Size >1 cm

Size <1 cm

Increase in size on interval CT scan

Stable or decrease in size on interval CT scan

Irregular or spiculated margin

Smooth, well-defined margins

Distortion of adjacent vessels (‘corona radiata’ sign)

Benign pattern of calcification

Cavitation with thick irregular walls

Cavitation with thick, smooth walls

Increased enhancement with contrast

Lack of contrast enhancement

Increased FDG uptake on CT-PET

Low FDG uptake on CT-PET

Table 9.6 lists the radiological features of benign and malignant lung lesions.

Solitary pulmonary nodules are common, and approximately 150000 per year are found with imaging. A SPN is a discrete, well-marginated, rounded opacity, less than or equal to 3 cm in diameter which is surrounded by lung parenchyma, does not touch the hilum or mediastinum, and has no associated atelectasis or pleural effusion.

The majority of SPNs are asymptomatic, detected incidentally and are benign, but this can only be determined after investigations as 20—30% of lung cancers present as SPNs. Solitary lung metastasis from other primary tumours can also occur. Carcinoid tumour of the lung can also present as a SPN and is discussed later in this chapter.

A SPN should be investigated according to the clinical symptoms, signs, and appearance on CT scan. In smokers with a risk of lung cancer, a SPN should be considered as malignant unless otherwise proven and patients should have a full staging CT scan of thorax, abdomen and pelvis, CT-PET scan, and a CT-guided biopsy. Measurement of tumour markers, such as PSA, CA 125, CEA and Ca99, may be indicated if metastases from other tumours is suspected. Table 9.7 outlines the risk of a SPN being malignant or benign.

Table 9.7 Risk factors for malignancy.

Low (<5%) Intermediate (5-65%) High (>65%)

Young patient

Mixture of low and high probability features

Older patient

Minimal smoking history

 

Heavy smoking history

No history of malignancy

 

Previous malignancy

Small nodule size

 

Larger nodule size

Regular margin

 

Irregular margin

Non-upper lobe

 

Upper lobe location

The Fleischner Society Guidelines for the management of SPNs < 1 cm in diameter are applied to SPNs according to whether the patient has a high or low risk for lung cancer. Table 9.8 outlines the guidelines. The WHO performance status of the patient, lung function, and extent of emphysema on CT should be taken into consideration before attempting a CT-guided biopsy. It should also be remembered that CT and CT-PET constitute a lot of radiation, and the pros and cons of following nodules up with repeated imaging should be discussed clearly with the patient.

Common causes of SPN and benign lung mass

A hamartoma is the commonest benign tumour of the lung, usually measuring <4 cm and asymptomatic. It is composed of epithelial tissue, fibrous tissue, cartilage, and fat and is described as having ‘popcorn calcification on a chest X-ray (Figure 9.19).

A tuberculous granuloma is a small, usually calcified nodule, often in the lung apex (Figure 9.20, Figure 9.21). There may be radiological changes suggestive of previous tuberculosis, such as apical fibrosis.

A non-tuberculous granuloma is usually an incidental finding in patients with sarcoidosis and other granulomatous disease,

An arterio-venous malformation (AVM) can look like a SPN on imaging and can present with haemoptysis. A pulmonary angiogram may be required to make the diagnosis. See Chapter 11 for the diagnosis and management of AVM.

Lung sequestration, or rounded atelectasis, can present as a pleurally-based mass associated with pleural thickening and with characteristic radiological features.

Other causes of SPN include pulmonary infarction, mucoid impaction in patients with asthma or bronchiectasis and rheumatoid nodules.

Cavitating lung lesions

There are many causes of a cavitating lung lesion. Malignant lesions, especially squamous cell carcinoma of the lung, can cavitate. Infective causes include lung abscess, fungal infections (aspergilloma, histoplasmosis, actinomycosis), bacterial infections (Klebsiella pneumonia, Staphylococcus aureus, and Mycobacterium tuberculosis'), and parasitic infections (hydatid) are discussed in Chapter 8. Granulomatosis with polyangiitis is discussed in Chapter 11.

Carcinoid tumour

Carcinoid tumours are rare tumours arising from neuroendocrine cells (Figure 9.22). The majority are non-malignant, grow slowly and rarely spread to other parts of the body. Some 85% of carcinoid tumours occur in the gastrointestinal tract, 10% in the lung, 3% in the pancreas and 2% in the kidney, ovary, and testis (Figure 9).

Table 9.8 Fleischner Society Guidelines for management of SPN, 2017.

Type of nodule

Size (mm)

Number of nodules

Risk of malignancy

Follow-up interval for CT

Solid

<6

Single

Low

No routine follow-up

Solid

<6

Single

High

Optional CT at 12 months

Solid

<6

Multiple

Low risk

No routine follow-up

Solid

<6

Multiple

High risk

Optional CT at 12 months

Solid

6-8

Single

Low risk

6-12 months, then consider CT at 18-24 months

Solid

6-8

Single

High risk

6-12 months, then consider CT at 18-24 months

Solid

6-8

Multiple

Low risk

3-6 months, then consider CT at 18-24 months

Solid

6-8

Multiple

High risk

3-6 months, then CT at 18-24 months

Solid

>8

Single

All

CT in 3 months or PET/CT or biopsy

Solid

>8

Multiple

Low risk

CT at 3-6 months, then consider CT at 18-24 months

Solid

>8

Multiple

High risk

CT at 3-6 months, then CT at 18-24 months

Subsolid:

Ground-glass

< 6

Single

All risk

No follow-up needed

Subsolid:

Ground-glass

>6

Single

All risk

CT 6-12 months to confirm presence then at 3 years and 5 years

Part-solid

<6

Single

All risk

No follow-up indicated

Pat-solid

>6

Single

All risk

CT 3-6 months to confirm presence then annual for 5 years

Subsolid: Multiple

<6

Multiple

All risk

CT at 3-6 months, If stable CT at 2 and 4 years

Subsolid: Multiple

>6

Multiple

All risk

CT at 3-6 months. Subsequent management based on most suspicious nodule

Carcinoid tumours of the lung account for 1—2% of all lung malignancies and occur equally in men and women, mainly in 40-50-year-olds. The majority are endobronchial and present with symptoms of cough, haemoptysis, wheeze, and breathlessness. Some 25% are found incidentally as a SPN in the peripheral parenchyma. A CT scan will confirm a nodule or mass in the thorax (Figure 9.23). A CT-PET is not very sensitive for detecting carcinoid, with only 75% sensitivity (Figure 9.24). At bronchoscopy the carcinoid tumour appears smooth and red. There is an increased risk of bleeding if biopsied. Typical carcinoids (5—15%) can metastasize to local lymph nodes, have a 5-year survival of 100% and a 10-year survival of 87%.

Some 1% of patients with carcinoid tumour of the lung develop the carcinoid syndrome due to the release of large amounts of serotonin, resulting in flushing of the skin, abdominal cramps, diarrhoea, wheeziness, palpitations, and hypotension (Figure 9.25). The carcinoid syndrome is more likely if the tumour has spread to the liver. A diagnosis of carcinoid syndrome can be made by an octreotide scan or somatostatin receptor scintigraphy. High levels of serotonin and chromogranin A can be measured in the blood, and high levels of 5 hydroxy-indole acetic acid (the product of serotonin metabolism) can be measured in a 24-hour urine collection.

Figure 9.19 CT thorax showing a hamartoma with the typical popcorn calcification.

Figure 9.20 CXR showing granulomas in the right lung.

Figure 9.21 CT thorax showing a calcified granuloma in the right lung.

Figure 9.22 CT showing round atelectasis which looks like a solitary pulmonary nodule.

Figure 9.23 CT thorax of carcinoid tumour of the lung.

Figure 9.24 PET scan of carcinoid tumour showing low FDG uptake.

Figure 9.25 Histology of carcinoid tumour.

Carcinoid tumour presenting as a SPN in the lung can be resected if there is no evidence of spread. Somatostatin analogues, octreotide, and lanreotide, can control the symptoms of carcinoid syndrome.

Malignant carcinoid tumours show areas of focal necrosis, with 48% metastasising to lymph nodes and 20% metastasising to distant sites. These have a 5-year survival of 69% and a 10-year survival of 52%. Somatostatin analogues, either alone or in combination with chemotherapy, can be considered for malignant lesions. Targeted radiotherapy and interferon can be effective in a significant number of patients with symptoms.

Future developments

Lung cancer remains a fatal disease in most patients. Lung cancer screening using low dose CT scanning in patients at risk may improve early detection. Studies are underway to see of this is safe and cost- effective. Much research is being done on targeted molecular therapies and gene expression profiling to determine response to treatment. This may translate into more individualised treatment for patients.

 Lung cancer is the commonest fatal malignancy in men and women in the UK, responsible for 40 000 deaths each year.

 The symptoms and signs of lung cancer may be non-specific, so patients and all healthcare professionals should be educated about these.

 Emphasis should be placed on smoking avoidance and smoking cessation as these are the only measures that will significantly reduce the incidence of lung cancer.

 The diagnosis of lung cancer is made with CT and CT-PET imaging for staging, and histological diagnosis.

 An assessment of the patient’s fitness for treatment includes lung function testing, cardiac testing, and calculation of the WHO performance status.

 Early detection of lung cancer can improve survival as these patients can be offered radical treatment.

 Patients with lung cancer should be discussed in a lung MDT and the diagnosis communicated sensitively to the patient and family.

 Surgical resection offers the best chance of survival in a patient with NSCLC.

 Multimodality treatments are available for all stages of lung cancers in both SCLC and NSCLC, which in trials have resulted in symptom relief and prolonged survival.

 New inhibitors for NSCLC have shown benefit in patients with Stage IV NSCLC and approved by NICE.

 Solitary pulmonary nodules have a wide differential and should be managed with careful history, examination, imaging, and biopsy if indicated.

MULTIPLE CHOICE QUESTIONS

9.1 What is the commonest histological type of lung cancer?

A Adenocarcinoma

B Bronchoalveolar cell carcinoma

C Large cell carcinoma

D Small cell carcinoma

E Squamous cell carcinoma

Answer: E

Squamous cell lung cancer is still the commonest lung cancer, although adenocarcinoma is now increasing in frequency, possibly reflecting the type of filters used in cigarettes.

9.2 Passive smoking increases the risk of lung cancer by how many times?

A 1x

B 1.5x

C 2x

D 4x

E 10x

Answer: B

Passive smoking increases the risk of lung cancer by 1.5x. This evidence has led to the banning of smoking in public places. A history of significant passive smoking should be elicited from all patients.

9.3 What is the overall 5-year survival for Stage IA NSCLC?

A 10%

B 20%

C 35%

D 50%

E 70%

Answer: D

The latest figures from Cancer Research UK suggest that the overall 5-year survival for Stage IA NSCLC is only 50%.

9.4 What is the 5-year survival after surgery for Stage IA NSCLC?

A 20%

B 30%

C 50%

D 70%

E 90%

Answer: D

Patients who have surgery for Stage IA NSCLC have a better outcome, with 70% surviving five years. These patients are not currently offered adjuvant chemotherapy.

9.5 Testing for EGFR mutational status is recommended for patients with which condition?

A Adenocarcinoma

B Carcinoid tumour

C Non-small cell lung cancer

D Small cell lung cancer

E Squamous cell carcinoma

Answer: A

All patients with an adenocarcinoma should have EGFR testing. EGFR is over-expressed in non-smokers with adenocarcinoma and particularly in women. These patients may respond to EGFR inhibitors.

9.6 Which feature of a solitary pulmonary nodule suggests that it might be malignant?

A Calcification

B Less than 1 cm in diameter

C Low FDG uptake on PET scan

D Smooth margins

E Thick-walled cavity

Answer: E

The other features suggest a benign aetiology.

9.7 Which is the commonest benign lung mass?

A Arteriovenous malformation

B Bronchogenic cyst

C Carcinoid tumour

D Granuloma

E Hamartoma

Answer E

A hamartoma is the commonest benign lung mass. It is described as having ‘popcorn calcification’ on the chest X-ray.

9.8 Pulmonary carcinoid tumours are associated with the carcinoid syndrome in what percentage of cases?

A 1%

B 5%

C 10%

D 25%

E 50%

Answer: A

Pulmonary carcinoids are usually benign and only 1% are associated with the carcinoid syndrome.

9.9 A 52-year-old man with a 30-pack year history of smoking goes to his GP with a one- month history of a persistent, dry cough. He has no other symptoms of concern. Clinical examination is normal. What should his GP do?

A Reassure him and advise him to stop smoking

B Prescribe oral antibiotics for 7 days

C Refer him to smoking cessation clinic and organise a chest X-ray

D Organise a CT thorax

E Refer urgently to a respiratory physician

Answer: C

All smokers with a persistent cough require a chest X-ray as cough is the commonest symptom of lung cancer. These patients should be strongly advised to stop smoking and referred to a smoking cessation clinic.

9.10 A 52-year-old woman is referred to the respiratory outpatient clinic with a 6-week history of a cough productive of a copious amount of white sputum, chest discomfort, breathlessness, and a weight loss of 5 kg. She had been a smoker of five cigarettes per day from the age of 17 until 20 years. Her GP had given her oral amoxicillin for 2 weeks followed by oral clarithromycin and prednisolone, 30 mg for 2 weeks without any improvement in her symptoms. Sputum samples have not grown any organisms. Her chest X-ray shows persistent consolidation in the left lower lobe. What would you be concerned about?

A Adenocarcinoma in situ

B Atypical pneumonia

C Mesothelioma

D Organising pneumonia

E Mycobacterium tuberculosis

Answer: A

This presentation and imaging mean that adenocarcinoma in situ is a possibility and should be actively excluded by obtaining histology.

9.11 A 55-year-old man with a 60-pack year history of smoking is admitted through Accident and Emergency Department with weakness, confusion, and after he had collapsed at home. His wife reported that he had been unwell for several months, unable to work, and complained of lethargy, weakness, and a cough. He had lost 10 kg in weight and appeared cachectic. A CT head was normal. Chest X-ray was not normal. Blood results were as follows: Hb 9.9 g dl-1, WCC 4.3, platelets 199, Na + 122, K+ 4.1, Urea 8.1, creatinine 100, EGFR >60. What is the most likely diagnosis?

A Adenocarcinoma of lung

B Carcinoid tumour

C Large cell poorly differentiated tumour

D Small cell carcinoma

E Squamous cell carcinoma of lung

Answer: D

This patient has presented with a SIADH. SCLC is associated with ectopic secretion of ADH.

9.12 A 70-year-old woman is found to have a nodule on a chest X-ray which was performed routinely prior to a left hip replacement. She has smoked 10 cigarettes per day for 20 years but had stopped 30 years previously. Apart from osteoarthritis of her left hip and a BMI of 40, she appeared well with no other symptoms. The orthopaedic consultant organised a CT scan of thorax and has referred her to you for advice about the nodule. The CT scan shows a 6 mm nodule in the left upper lobe of the lung with no lymphad- enopathy. The nodule is described as smooth with no calcification by the consultant radiologist. How would you manage this patient?

A Reassure and discharge the patient

B Organise a CT guided biopsy

C Organise a bronchoscopy for bronchoal- veolar lavage

D Organise a CT-PET scan

E Arrange for an interval CT scan of thorax in 6 months

Answer: E

All SPNs in the lung may be malignant, especially in someone over the age of 40 years and who has a smoking history. This nodule is only 6 mm and smooth and was found incidentally. It will not be easy to biopsy, especially in someone with a BMI of 40. It may also be too small for CT-PET resolution. As she is asymptomatic and stopped smoking some time ago, she is in the low risk group. The Fleischner Society guidelines recommends an interval CT scan in 12 months to see if it changes.

FURTHER READING

American College of Chest Physicians (ed.) (2013). Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 143 (5): 1S-50S.

Cancer Research UKs (2016) [online].. Doll, R. and Hill, A.B. (1954). The mortality of doctors in relation to their smoking habits. British Medical Journal 1 (4877): 1451-1455.

Gould, M.K., Fletcher, J., Iannettoni, M.D. et al. (2007). Evaluation of patients with pulmonary nodules: when is it lung cancer?: ACCP evidence- based clinical practice guidelines (2nd edition). Chest 132 (3): 108S-130S.

MacMahon, H., Austin, J.H., Gamsu, G. et al. (2005). Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner Society. Radiology 237 (2): 395-400.

Macmillan Cancer Support (n.d.) Home - Macmillan Cancer Support, 2016 [online]. Available at: www. macmillan.org.uk (accessed 11 March 2017).

National Institute for Health and Care Excellence (2011). Lung cancer: diagnosis and management. NICE Guideline (CG121), Clinical Guideline, (April), [online]. Available at: http://nice.org.uk/ guidance/cg121. Ost, D., Fein, A.M., and Feinsilver, S.H. (2003).

The solitary pulmonary nodule. New England Journal of Medicine 348 (25): 2535-2542.

Rami-Porta, R. and Crowley, J.G.P (2009). The revised TNM staging system for lung cancer. Annals of Thoracic and Cardiovascular Surgery 15 (1): 4-9.

Rivera, M., Mehta, A., and American College of Chest Physicians (2007). Initial diagnosis of lung cancer: ACCP Evidence-Based Clinical Practice Guidelines (2nd edition). Chest 132 (3 Supplement): 131S-148S.


If you find an error or have any questions, please email us at admin@doctorlib.info. Thank you!