1

What is non-small cell lung cancer?

Non-small cell lung cancer (NSCLC) is classified by the World Health Organization (WHO) and International Association for the Study of Lung Cancer (IASLC) into different histological subtypes (Table 1) that exclude small cell lung cancer (SCLC).

The common histological subtypes include:

a)

adenocarcinoma (40% of lung cancers);

b)

squamous cell carcinoma (25% of lung cancers);

c)

large cell carcinoma (10% of lung cancers).

2

Describe the revised lung adenocarcinoma sub-classification (Table 2)

This major revision of the classification of adenocarcinomas was proposed in 2011 by a multidisciplinary expert panel representing the IASLC, American Thoracic Society and European Respiratory Society, in particular to eliminate the term ‘bronchoalveolar carcinoma’.

3

How are the pathological subtypes of NSCLC distinguished?

Morphology:

a)

adenocarcinoma is characterised by a normal glandular structure, when well differentiated, and positive mucin staining (Figure 1);

b)

squamous cell carcinoma is characterised by keratin pearls and intercellular bridges when well differentiated (Figure 2);

c)

large cell carcinoma is characterised rather by the absence of morphological features of the other histologic types, with the differential diagnosis of SCLC. Large cell carcinoma is differentiated from SCLC by a larger size of cells, a lower nuclear: cytoplasm ratio and coarser chromatin;

d)

SCLC is distinguished from NSCLC by small, round cells with little cytoplasm and hyperchromatic nuclei.

Immunohistochemistry:

a)

adenocarcinoma:

i)

thyroid transcription factor-1 (TTF-1) (89%);

ii)

p63 (32%);

iii)

cytokeratin 5/6 (18%);

iv)

34βE12 (82%);

b)

squamous cell carcinoma:

i)

TTF-1 negative;

ii)

p63 diffuse;

iii)

cytokeratin 5/6 diffuse;

iv)

34βE12 diffuse.

Although reactivity for ‘squamous markers’ is common in lung adenocarcinoma, a two-marker panel of TTF-1/p63 subtype can distinguish the majority of tumours as adenocarcinoma, as compared to squamous cell carcinoma. The addition of cytokeratin 5/6 is required in a small number of cases to confirm the subtype.

Molecular studies.

4

What is the epidemiology of lung cancer?

Lung cancer is the commonest cause of cancer and is the leading cause of cancer-related death worldwide.

The incidence is highest in Europe and North America and lowest in Africa.

The varying incidence reflects rates of smoking, with smoking-related lung cancer accounting for 85-90% cases.

Lung cancer has a male: female ratio of 6:5.

The incidence of lung cancer increases with age, with 75% of patients presenting over the age of 65.

Recently in the United Kingdom and Europe, the male incidence rates have decreased, whilst female incidence rates have increased, which reflects previous smoking patterns.

Most patients present with advanced disease.

5

What are the risk factors for NSCLC?

85-90% of cases have a positive smoking history.

Occupational exposure including asbestos, silica and uranium.

Radon gas.

Air pollution.

Previous radiotherapy to lungs.

Genetic – hereditary susceptibility has been demonstrated in a number of studies. The 15q24-25 regions encode for the nicotinic acetylcholine receptor subunit genes that play a role in nicotine addiction. Whilst nicotine does not induce cancer, its promotion of proliferation and growth of cancer cells may support tumour growth.

6

What is the pathogenesis of NSCLC?

Although the exact pathogenesis of NSCLC is incompletely understood, a number of factors are thought to play a role, including:

a)

tumour suppressor gene inactivation;

b)

oncogene activation;

c)

activation of proliferation;

d)

evasion of apoptosis;

e)

angiogenesis;

f)

suppression of immune response.

7

Which genetic mutations are thought to be involved in the pathogenesis of NSCLC?

Epidermal growth factor receptor (EGFR) protein is responsible for the stimulation of tyrosine kinase and activation of cell growth and survival pathways. EGFR mutations are:

a)

seen more frequently in never smokers, females and Asians;

b)

identified in 23% of cases of adenocarcinoma;

c)

associated with an increased sensitivity to EGFR tyrosine kinase inhibitors (TKIs), including erlotinib and gefitinib.

Kirsten rat sarcoma viral (KRAS) protein-stimulated signalling pathways are downstream from EGFR and promote cell growth. EGFR TKIs, however, cannot block the mutated KRAS protein and these patients are resistant to erlotinib and gefitinib. KRAS mutations are:

a)

identified in 25% of adenocarcinomas and 5% of squamous cell carcinomas;

b)

more common in smokers and Caucasians;

c)

associated with poorer survival despite targeting therapy.

Anaplastic lymphoma kinase (ALK) protein is associated with abnormal cell proliferation. ALK mutations:

a)

occur in 6% of adenocarcinomas;

b)

are more common in never smokers and younger patients;

c)

confer sensitivity to crizotinib in locally advanced or metastatic disease and resistance to EGFR TKIs.

B-rapidly accelerated fibrosarcoma (BRAF) protein is responsible for triggering the mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) pathway involved in cell division and differentiation. BRAF mutations are:

a)

identified in 3% of adenocarcinomas;

b)

more common in smokers.

Hepatocyte growth factor receptor (MET) amplification may result in tumour growth, angiogenesis and metastatic spread to tumour cells. MET mutations are:

a)

identified in 5% of NSCLC and 2% of adenocarcinomas;

b)

more common in male smokers;

c)

identified in 20-30% of acquired resistance to EGFR inhibitors suggesting a role for combination therapy in these patients.

Other mutations include:

a)

Human epidermal growth factor receptor 2 (HER2);

b)

MAPK/ERK kinase 1 (MEK1);

c)

Neuroblastoma rat sarcoma viral (NRAS);

d)

Alpha serine/threonine-protein kinase (AKT1).

Where present, 95% of these mutations are mutually exclusive.

8

Which paraneoplastic syndromes are associated with NSCLC?

Paraneoplastic syndromes occur in 13% of patients with NSCLC and include:

a)

hypertrophic pulmonary osteoarthropathy (HPOA) – which is defined by digital clubbing and distal periostitis of long bones and associated with adenocarcinoma;

b)

hypercalcaemia – which is typically associated with squamous cell carcinoma;

c)

acanthosis nigricans – which is associated with adenocarcinoma and squamous cell carcinoma.

The mechanisms for these syndromes are not known but neurological, vascular and hormonal pathways have been proposed.

9

What are the symptoms of NSCLC?

Effects of the primary tumour within the chest:

a)

cough;

b)

dyspnoea;

c)

persistent pneumonia;

d)

haemoptysis;

e)

chest pain;

f)

shoulder and arm pain (associated with superior sulcus tumours).

Effects of metastases within the chest:

a)

effects of extrinsic compression of lymph node metastases:

i)

dyspnoea or wheeze due to airway obstruction;

ii)

superior vena cava obstruction (SVCO);

iii)

hoarse voice due to recurrent laryngeal nerve invasion;

b)

dyspnoea due to pleural effusion, pericardial effusion or pulmonary metastases.

Effects of distant metastases (in order of frequency):

a)

brain – headache, seizure and symptoms of raised intracranial pressure. The brain is the commonest site of NSCLC metastases, which are symptomatic in most patients;

b)

bone – pain, commonly back, ribs and long bones;

c)

liver – usually asymptomatic or pain due to distension of the liver capsule;

d)

adrenal – usually asymptomatic but may cause symptoms of adrenal insufficiency or haemorrhage;

e)

lung – dyspnoea or haemoptysis.

Paraneoplastic effects.

10

What are the signs of NSCLC?

Effects of the primary tumour within the chest:

a)

chest wall tenderness;

b)

Horner’s syndrome and atrophy of the small muscles of the hand in association with superior sulcus tumours.

Effects of metastases within the chest:

a)

effects due to extrinsic compression of lymph node metastases:

i)

supraclavicular lymphadenopathy;

ii)

cyanosis and upper body swelling due to SVCO;

b)

stony dullness and absence of breath sounds due to pleural effusion or pulmonary metastases;

c)

raised jugular venous pressure (JVP), hypotension and quiet breath sounds due to pericardial effusion.

Effects of distant metastases:

a)

brain – localising neurological signs, cerebellar signs and papilloedema (in the case of raised intracranial pressure);

b)

bone – tenderness along the spine, ribs and long bones;

c)

liver – hepatomegaly or ascites;

d)

adrenal – hypotension.

Paraneoplastic effects.

11

Which blood tests are used to investigate a patient with NSCLC?

Although radiology and histology are the mainstay in the diagnosis of NSCLC, some blood tests can be used to detect metastatic or paraneoplastic disease.

Full blood count (FBC) – pancytopaenia may indicate the presence of bone marrow involvement.

Liver function tests (LFTs) – which may be abnormal in the presence of hepatic metastases.

Serum calcium and alkaline phosphatase (ALP) levels – which may be raised in the presence of bone metastases.

12

What are the radiological features of NSCLC (Figure 3)?

Chest radiograph (CXR) – which may demonstrate the presence of:

a)

primary tumour – hilar, mediastinal or parenchymal mass;

b)

lymph node involvement – hilar enlargement;

c)

metastatic disease – deposits in the contralateral lung;

d)

pleural effusion;

e)

obstructive pneumonia or atelectasis.

Computed tomography (CT) scan of the thorax, abdomen and pelvis (Figure 4) – to determine:

a)

size, site and local spread of the primary lesion;

b)

lymph node involvement;

c)

presence of metastatic disease – including liver, bone and adrenals.

Distinguishing T3 from T4 staging on CT – sensitivity 55%, specificity 89%.

N1 staging by CT – sensitivity 62%, specificity 88%.

N2 staging by CT – sensitivity 79%, specificity 78%.

Magnetic resonance imaging (MRI) is superior to CT at assessing:

a)

brain metastases;

b)

superior sulcus tumours (Figure 5);

c)

brachial plexus involvement;

d)

vascular involvement;

e)

vertebral invasion;

f)

chest wall invasion (sensitivity 90%, specificity of 86%).

Further evaluation of indeterminate lesions identified in the brain, liver and adrenals on CT should be undertaken by MRI.

Positron emission tomography (PET) in combination with CT scanning (PET-CT) (Figure 6) – which should be performed if the patient is being considered for surgery or radical therapy to detect the presence of metastatic disease.

PET-CT is a useful adjunct for T staging where associated distal collapse is present.

PET-CT for N staging – sensitivity 90%, specificity 96%.

PET-CT for M staging – sensitivity 93%, specificity 96% (except sensitivity for detecting brain metastases is only 60%).

13

What accounts for the false-positive and false-negative rate associated with PET-CT?

False-negative scans may occur due to:

a)

low uptake in primary lesions, such as carcinoid or lepidic predominant tumours;

b)

misregistration due to a breathing artifact;

c)

uncontrolled diabetes;

d)

lesions <8mm.

False-positive scans occur in the presence of inflammatory or infectious lesions, including sarcoid, tuberculosis, histoplasmosis, rheumatoid nodules and reactive nodes from obstructive pneumonitis. In particular, a sarcoid-like reaction is frequently seen in the intrathoracic lymph nodes of patients with primary lung cancer.

14

What information from radiological investigation other than TNM staging influences prognosis?

Tumours with a high maximal standardised uptake value (SUV) are associated with poorer long-term survival.

Diffuse bone marrow uptake in the absence of focal bony metastases is also associated with worse outcome.

15

What is the evidence for screening in NSCLC?

Early trials of intensive versus less intensive chest radiograph screening, with or without sputum cytology, failed to reduce mortality from lung cancer.

CT scanning, however, has been shown to reduce mortality in high-risk patients in a large US trial (see below), with results of screening in UK populations awaited.

16

What did the NLST study show?

NLST = National Lung Screening Trial.

The NLST study was a prospective, randomised controlled trial between 2002 and 2004, reporting in 2011, assessing patients at high risk for lung cancer in the USA.

Patents deemed to be at high risk for lung cancer included current smokers with a cigarette smoking history of at least 30 pack-years or former smokers who quit within the previous 15 years.

The patients (n=53,454) were randomised to either:

a)

group I (n=26,722) – three annual screenings with low-dose CT;

b)

group II (n=26,732) – single-view posteroanterior CXR.

For those undergoing CT screening, the study demonstrated:

a)

relative reduction in mortality from lung cancer of 20%;

b)

6.7% reduction in rate of death from any cause.

17

What are the changes to the TNM descriptors in the 7th edition of the TNM classification for NSCLC?

In 2010, the American Joint Cancer Committee/Union for International Cancer Control (AJCC/UICC) adopted the 7th edition of the TNM staging system, as proposed by the International Association for the Study of Lung Cancer (IASLC), as the standard by which all patients with NSCLC should be staged.

T1 tumours are subclassified according to new size criteria – T1a ≤2cm and T1b >2cm but ≤3cm.

T2 tumours are subclassified according to new size criteria – T2a >3cm but ≤5cm and T2b >5cm but ≤7cm.

T3 tumours are classified according to new size criteria – T3 >7cm.

The presence of an additional tumour nodule in the same lobe has been reclassified from T4 to T3.

The presence of an additional tumour nodule in an ipsilateral lobe has been reclassified from M1 to T4.

The presence of an additional tumour nodule in a contralateral lobe has been reclassified from M1 to M1a.

The presence of a malignant pleural/pericardial effusion or nodules has been reclassified from T4 to M1a.

The presence of distant metastases has been reclassified from M1 to M1b.

18

Describe the AJCC/UICC 7th edition of the TNM classification for NSCLC (Table 3)