Non-Small Cell Lung Cancer (NSCLC)

Adenocarcinoma

• Most common type of NSCLC and the predominant subtype among non-smokers
• Originates from glandular epithelial cells, often in peripheral lung parenchyma
• Subtypes include lepidic, acinar, papillary, micropapillary, and solid patterns
• Precursor lesions include atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS)
• AIS may evolve to minimally invasive adenocarcinoma (MIA) and subsequently to invasive adenocarcinoma
• Sub-solid nodules or ground-glass opacities on CT often correlate with early-stage lesions

Squamous Cell Carcinoma

• Strongly associated with tobacco smoking
• Historically the most frequently diagnosed lung cancer subtype
• Typically originates in the central bronchi but now increasingly seen in the periphery
• Characterised histologically by keratinisation and intercellular bridges
• Can present with cavitation and may be associated with paraneoplastic hypercalcaemia

Large Cell Carcinoma

• Considered a diagnosis of exclusion
• Poorly differentiated tumour lacking squamous or glandular differentiation
• Typically arises as a large peripheral mass
• Many previously diagnosed cases are now reclassified using immunohistochemistry and molecular markers
• Includes large cell neuroendocrine carcinoma if neuroendocrine differentiation is detected

WHO Classification Framework

• Based on the 2015 and 2021 WHO classifications of lung tumours
• Utilises light microscopy, immunohistochemistry, and molecular genetic testing
• Enables subclassification of tumours to inform prognosis and therapy
• Recognises additional rare epithelial subtypes such as:
  • Adenosquamous carcinoma
  • Sarcomatoid carcinoma
  • Pulmonary blastoma
• Distinct category for neuroendocrine neoplasms including:
  • Large cell neuroendocrine carcinoma
  • Small cell carcinoma

Diagnostic and Prognostic Implications

• Histopathological classification determines tumour biology and guides treatment
• Adenocarcinomas are more likely to harbour targetable driver mutations such as EGFR, ALK, or ROS1 rearrangements
• Molecular testing is essential in advanced-stage disease for therapy selection
• Squamous cell carcinomas have a different mutation profile and are less likely to respond to targeted therapies
• Immunotherapy (e.g., checkpoint inhibitors) plays a major role in treatment, particularly in tumours lacking actionable mutations
• Accurate classification helps predict treatment response and long-term outcomes

Tobacco Smoking

• Tobacco smoking accounts for up to 90% of lung cancer cases in Europe and the United States.
• Cigarette smoke contains multiple carcinogens including polynuclear aromatic hydrocarbons, aromatic amines, and N-nitrosamines.
• Lung cancer risk is dose-dependent, increasing with the number of cigarettes smoked, duration of smoking, and tar/nicotine content.
• Risk is highest in current smokers and remains elevated for decades after cessation. Long-term studies show risk may persist for 30 years post-cessation.
• The susceptibility to tobacco-related carcinogenesis may differ between sexes, with women more likely to develop adenocarcinomas and possibly exhibiting distinct biological responses.
• Tobacco use and asbestos exposure act synergistically, with combined exposure increasing lung cancer risk up to 80–90 times above baseline.
• Although the link remains under investigation, emerging evidence suggests e-cigarette use ("vaping") may increase lung cancer risk due to the presence of known carcinogens in aerosols.

Second-hand Smoke Exposure

• Passive inhalation of cigarette smoke (second-hand smoke) can increase lung cancer risk by approximately 25%–30%.
• Urinary levels of tobacco-derived carcinogens in non-smokers exposed to second-hand smoke are 1–5% of those found in smokers.
• Second-hand smoke is thought to be responsible for around 3000 cases of lung cancer annually in the United States.

Radon Gas

• Radon is a radioactive gas formed by the decay of uranium in soil and rocks.
• It is a well-established occupational hazard in uranium miners, but also a domestic risk when it percolates into homes.
• Radon decays into alpha-particle-emitting progeny that damage DNA.
• Estimated to cause 2100 lung cancers annually in the U.S., and contributes to 9100 cases among smokers.

Asbestos Exposure

• Asbestos, particularly the silicate type, is a potent lung carcinogen.
• Associated not only with NSCLC but also with malignant mesothelioma and pulmonary fibrosis.
• Smoking and asbestos exposure have a synergistic effect, vastly increasing lung cancer risk.
• The latency period between exposure and cancer development can be several decades.

Outdoor and Occupational Air Pollution

• Chronic exposure to atmospheric pollutants such as polycyclic aromatic hydrocarbons, arsenic, chromium, cadmium, and nickel contributes to lung cancer risk.
• Occupational exposures to vinyl chloride, halogen ethers, and beryllium are also implicated.

Radiation Exposure

• Ionising radiation, including medical exposures such as therapeutic chest radiotherapy (e.g., for breast cancer or Hodgkin lymphoma), has been linked to lung cancer development.
• The risk is particularly elevated when combined with other factors like smoking.

Pulmonary Fibrosis

• Patients with idiopathic pulmonary fibrosis have a sevenfold increased risk of developing lung cancer, independent of smoking status.
• The fibrotic microenvironment may enhance malignant transformation.

HIV Infection

• Individuals with HIV have a 2–11-fold increased risk of developing lung cancer compared to the general population.
• Lung cancer in this group occurs at younger ages and is frequently advanced at presentation.
• The association appears to be independent of smoking, though the majority of cases occur in smokers.

Lung Cancer in Never-Smokers

• Approximately 10%–25% of lung cancers globally occur in individuals who have never smoked.
• These cancers often show a higher frequency of actionable mutations such as EGFR and ALK rearrangements and are more responsive to targeted therapies.
• Distinct from smoking-related NSCLC in their genetic, molecular, and clinical profiles.

Genetic Susceptibility and Sex Differences

• Genetic polymorphisms affecting DNA repair and carcinogen metabolism may modulate individual susceptibility.
• Women may be more susceptible to the carcinogenic effects of tobacco, and they often exhibit longer survival and better response to EGFR-targeted therapies.

Diet and Lifestyle Factors

• High cardiorespiratory fitness is associated with reduced lung cancer risk and improved outcomes among smokers and former smokers.
• While diets high in fruits and vegetables are associated with lower incidence, trials using beta-carotene supplementation paradoxically showed increased lung cancer risk, particularly in smokers.

Histological Subtypes

Adenocarcinoma

• Most common subtype of NSCLC in the United States and in individuals who have never smoked.
• Arises from bronchial mucosal glands or type II pneumocytes, frequently in the peripheral lung.
• Associated with pre-existing scars or inflammatory foci (“scar carcinoma”).
• Includes former bronchioloalveolar carcinoma (BAC), now classified under adenocarcinoma with lepidic growth.
• The lepidic variant follows alveolar septa and appears radiologically as ground-glass opacities or consolidation.
• Subtypes: atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma.
• AIS and MIA are excellent prognostic forms, often discovered as sub-solid nodules with limited invasive potential.

Squamous Cell Carcinoma (SCC)

• Constitutes 25–30% of NSCLC.
• Typically arises in the central bronchi and presents as cavitary lesions.
• Histologically characterised by keratin pearls and intercellular bridges.
• Associated with smoking and often diagnosed via cytology due to its tendency to exfoliate.
• Frequently linked with paraneoplastic hypercalcaemia.

Large Cell Carcinoma

• Comprises approximately 8–15% of NSCLC.
• Poorly differentiated and lacks squamous or glandular features.
• Histologically shows large sheets of atypical cells with necrosis.
• Usually presents as a large peripheral mass.
• Improved immunohistochemistry has reclassified many of these as poorly differentiated adenocarcinoma or SCC.

Sarcomatoid Carcinoma

• A rare and aggressive variant of NSCLC.
• Histologically shows spindle and/or giant cell components.
• Often resistant to conventional therapy.

Carcinogenesis and Environmental Exposures

• NSCLC development involves accumulation of genetic mutations resulting from repeated toxic insults.
• Tobacco smoke is the principal carcinogen, containing over 300 harmful chemicals and at least 40 potent carcinogens.
• Notable agents include:
  • Polyaromatic hydrocarbons
  • Nicotine-derived nitrosamine ketone (NNK) – causes DNA adduct formation
  • Benzo[a]pyrene – activates signalling pathways like AKT and induces mutations in tumour suppressors such as p53
• Occupational and environmental carcinogens contribute significantly:
  • Asbestos (synergistic with tobacco)
  • Radon (implicated in 10% of cases)
  • Outdoor air pollution (1–2% of cases)
  • Chronic lung diseases like idiopathic pulmonary fibrosis and COPD increase risk

Genetic and Molecular Pathogenesis

• Tumourigenesis involves activation of oncogenes and inactivation of tumour suppressor genes.
• Common mutations in NSCLC include:
  • KRAS: Seen in ~30% of adenocarcinomas, strongly associated with smoking, and carries prognostic and therapeutic implications
  • EGFR: More common in never-smokers and Asian populations; predictive of response to EGFR tyrosine kinase inhibitors
  • TP53 and Rb: Frequently mutated tumour suppressors in NSCLC
  • Other oncogenes: c-MYC and c-RAF amplifications have been reported

Intratumour Heterogeneity

• Lung cancers accumulate diverse subclonal mutations before clinical presentation.
• Studies show early mutations can occur decades before diagnosis, especially in former smokers.
• APOBEC-mediated mutagenesis may dominate in later tumour evolution.
• High subclonal diversity correlates with resistance to therapy and poor prognosis.

Natural History and Tumour Behaviour

• NSCLC follows a progression from early clonal mutations to rapid expansion driven by secondary genomic changes.
• The “multiple hit” theory postulates that cumulative insults disrupt genomic integrity, leading to malignant transformation.
• Tumour progression disrupts local anatomy and compromises respiratory function, producing clinical symptoms such as cough, haemoptysis, chest pain, and dyspnoea.
• The biological latency between early mutations and aggressive clinical behaviour explains late diagnosis in many cases.

Global Burden

• Lung cancer was responsible for approximately 1.8 million deaths worldwide in 2020, making it the most common cause of cancer death globally.
• In 2022, an estimated 2.5 million new cases of lung cancer were diagnosed globally, accounting for about 12.4% of the total cancer burden.
• Industrialised regions such as Eastern Asia, North America, and Europe report the highest incidence rates, while the lowest rates are seen in regions like Western Africa.
• Global trends in lung cancer closely follow patterns of tobacco use with a latency period of several decades. Declining incidence has been observed in countries with successful tobacco control, such as the United States, Canada, Australia, and the United Kingdom.
• In contrast, lung cancer incidence is expected to increase in developing countries due to rising smoking rates, notably in China and India.

United States Statistics

• Lung cancer is the second most commonly diagnosed cancer in the US (after prostate in men and breast in women) but remains the leading cause of cancer death.
• In 2024, it was estimated that 234,580 new cases would be diagnosed and 125,070 deaths would occur.
• Approximately 87% of new lung cancer cases are expected to be NSCLC.
• Lung cancer incidence correlates closely with smoking history. Individuals with a 40 pack-year smoking history have a 20-fold increased risk compared to non-smokers.
• From 2012 to 2021, incidence rates decreased by 3.0% annually in men and 1.4% in women, reflecting lagging trends in smoking cessation among women.
• Lung cancer mortality rates fell by 4.2% per year from 2014 to 2023, driven by earlier detection (e.g. through screening) and advances in therapy.
• By 2065, the age-adjusted lung cancer mortality rate is projected to decline by 79% relative to 2015 figures.

Age and Sex Distribution

• The median age at lung cancer diagnosis in the US is 71 years.
• Incidence increases steadily after age 40 and peaks in those over 70 years.
• Historically, lung cancer has been more common in men, but recent data show rising rates in women, particularly those under 55 years of age.
• This reversal may relate to changes in smoking habits among women born after 1965 and potential biological differences in susceptibility to carcinogens.
• Women tend to present with more localised disease, have a higher incidence of adenocarcinoma, and are generally younger at diagnosis than men.

Racial and Ethnic Disparities

• Among men, lung cancer incidence is higher in Black Americans (65.2 per 100,000) than in White Americans (58.2 per 100,000). Among women, the pattern is reversed: incidence is higher in Whites (51.2 per 100,000) compared to Blacks (43.1 per 100,000).
• These differences have historically been attributed to variations in tobacco use; however, recent evidence suggests biological susceptibility may also play a role.
• Five-year survival rates are estimated at 18% in Whites and 15% in Blacks.
• The disparity in survival is largely due to differences in stage at diagnosis and access to guideline-based treatment. When adjusted for stage and socioeconomic status, survival differences between Black and White patients are largely eliminated.

Temporal Trends and Smoking Correlation

• Declines in lung cancer incidence and mortality have been attributed to decreased tobacco use following public health interventions.
• In the US, the smoking prevalence dropped from over 40% in the 1960s to 11.5% in 2021. Despite this, 28.3 million US adults continued to smoke in 2021.
• Filtered cigarettes, introduced in the 1960s, have been speculated to influence the shift in histological subtype from squamous cell carcinoma to adenocarcinoma, though this remains unproven.
• In several countries, including the US and Canada, lung cancer rates have begun to plateau in women while continuing to decline in men.
• Notably, Chinese women demonstrate higher lung cancer incidence than European women despite having much lower smoking rates, indicating possible non-tobacco-related risk factors.

Cough

• Often the earliest and most common symptom in NSCLC, particularly in smokers or former smokers.
• Persistent or worsening cough may suggest endobronchial obstruction or post-obstructive pneumonia.
• Present in over half of all patients at diagnosis, and in some cases is the sole symptom.

Dyspnoea

• Can arise from various causes including central airway obstruction, pleural effusion, pneumonia, phrenic nerve dysfunction, or underlying COPD.
• Frequently associated with large or centrally located tumours.

Haemoptysis

• Typically presents as blood-tinged sputum rather than massive bleeding.
• Though less frequent than cough, its presence in smokers should raise strong suspicion of malignancy.
• May result from tumour invasion of bronchial vessels.

Chest and Shoulder Pain

• Chest discomfort is more often seen in peripheral tumours invading pleura or chest wall.
• Shoulder pain, especially when radiating and accompanied by neurological symptoms, may indicate a Pancoast tumour involving the brachial plexus.

Hoarseness

• Usually caused by recurrent laryngeal nerve palsy, especially on the left side due to its anatomical course through the mediastinum.
• May be intermittent or progressive and is more common with bulky central tumours.

Weight Loss and Cachexia

• Involuntary weight loss is a common systemic manifestation and strongly correlates with advanced disease.
• Often reflects increased metabolic activity and cytokine release from the tumour.

Dysphagia

• Occurs when large mediastinal lymph nodes or primary masses compress the oesophagus.
• May be worsened postprandially due to increased intrathoracic pressure.

Fatigue

• Commonly reported and multifactorial in origin.
• May result from anaemia, metabolic derangement, or systemic inflammation.

Bone Pain and Fractures

• Indicates metastatic spread to skeletal sites, typically involving the spine, pelvis, or long bones.
• May present as localised pain or pathological fractures.

Neurological Symptoms

• Brain metastases can present with seizures, confusion, behavioural changes, headaches, or focal deficits.
• Often occurs in later stages but may be the initial presentation in some.

Facial Swelling and Venous Distension

• Suggestive of superior vena cava (SVC) syndrome caused by compression from central tumours or lymphadenopathy.
• Can be accompanied by orthopnoea, facial plethora, or neck vein distension.

Pancoast Syndrome

• Characterised by severe shoulder or arm pain, muscle weakness, and paraesthesias due to brachial plexus invasion.
• May also be associated with Horner’s syndrome (ptosis, miosis, anhidrosis) from sympathetic chain involvement.

Asymptomatic Presentation

• Approximately 7–10% of cases are identified incidentally on imaging done for unrelated reasons.
• These patients may present with early-stage disease and better prognosis.

Risk Factors Identified Through History

Cigarette Smoking

• Most significant risk factor, responsible for up to 90% of lung cancers in developed countries.
• Includes current and former smokers; risk increases with duration and intensity of use.
• Exposure to second-hand smoke increases risk by 25–30%.

Chronic Obstructive Pulmonary Disease (COPD)

• Independently associated with increased lung cancer risk even after accounting for smoking history.
• Likely due to chronic inflammation, repeated epithelial injury, and impaired clearance mechanisms.

Family History

• First-degree relatives of lung cancer patients have approximately double the risk.
• Risk increases if the affected relative was diagnosed before age 60.

Radon Gas Exposure

• An odourless radioactive gas released from soil and building materials.
• Recognised cause of lung cancer, especially among non-smokers, and accounts for a notable proportion of residential cases.

Asbestos Exposure

• Occupational exposure is a known risk factor, with synergistic effects when combined with smoking.
• Increases risk for both lung cancer and mesothelioma.

Older Age

• Lung cancer predominantly affects individuals aged over 70 years.
• Diagnosis in individuals under 55 years remains uncommon, constituting fewer than 10% of cases.

Symptom Patterns Based on Tumour Location

Central Tumours

• Commonly squamous cell carcinomas.
• Symptoms include persistent cough, haemoptysis, wheezing, atelectasis, and post-obstructive infections.

Peripheral Tumours

• Often adenocarcinomas or large cell carcinomas.
• May be asymptomatic initially and later present with pleuritic chest pain, pleural effusion, or distant metastases.

Mediastinal Involvement

• Can lead to compression-related symptoms including hoarseness, dysphagia, stridor, or pericardial effusion.
• In some cases, causes chylothorax or palpitations due to thoracic duct or cardiac involvement.

Paraneoplastic Syndromes

• Occur in a subset of NSCLC patients, particularly with adenocarcinoma.
• Include hypercalcaemia (via PTHrP, most common in squamous cell carcinoma), syndrome of inappropriate antidiuretic hormone secretion (SIADH), Cushing syndrome (ectopic ACTH), hypertrophic pulmonary osteoarthropathy, clubbing, and Trousseau syndrome (thromboembolic events).

General Observations

• Patients may appear cachectic, in respiratory distress, or cyanosed.
• Up to 75% of patients are diagnosed at an advanced stage, often with evident signs of systemic illness including weight loss and fatigue.
• Fever may occasionally be present due to post-obstructive infection or tumour necrosis.

Respiratory System

• Findings vary by tumour location and extent of involvement.
• Central airway obstruction may result in decreased or absent breath sounds, wheeze, or stridor on the affected side.
• Peripheral tumours may cause dullness to percussion and reduced breath sounds due to lobar or segmental collapse or associated pleural effusion.
• Dyspnoea may manifest with accessory muscle use, tachypnoea, orthopnoea, or cyanosis.
• Wheezing and unilateral decreased air entry can occur due to bronchial obstruction or post-obstructive changes.
• Pleural effusions typically present with stony dullness, decreased breath sounds, and reduced tactile fremitus.

Head and Neck

• Examination may be normal unless there is nodal spread.
• Supraclavicular or cervical lymphadenopathy may be palpable in advanced disease.
• Ultrasound can detect non-palpable supraclavicular node involvement, aiding in staging.
• Horner’s syndrome (ptosis, miosis, anhidrosis) may be noted in apical tumours invading the sympathetic plexus (Pancoast tumours).

Cardiovascular System

• Signs of pericardial effusion may include muffled heart sounds, elevated jugular venous pressure, hypotension, or pulsus paradoxus, especially in large effusions or tamponade.
• Superior vena cava (SVC) syndrome may be evident with facial and upper extremity oedema, venous distension of the neck and anterior chest wall, plethora, cyanosis, papilloedema, or conjunctival oedema.
• Palpitations may occur in cases with pericardial or myocardial involvement.

Musculoskeletal System

• Tenderness on spinal percussion or over long bones may indicate osseous metastases.
• Signs of vertebral involvement may include point tenderness and pain exacerbated by movement.
• Pancoast tumours may present with shoulder and arm pain, wasting of hand muscles, or weakness in the C8/T1 distribution.
• Clubbing and hypertrophic pulmonary osteoarthropathy (painful swelling of wrists, ankles, or knees) may be seen, more frequently in adenocarcinoma.

Abdominal Examination

• Hepatomegaly, which may be tender, suggests hepatic metastases.
• Gastrointestinal symptoms such as early satiety, bloating, or altered bowel habits may reflect liver involvement or paraneoplastic pseudo-obstruction.

Neurological Examination

• Brain metastases may cause focal deficits, altered mental status, headache, papilloedema, or seizures.
• Spinal metastases can result in spinal cord compression, evidenced by back pain, reduced lower limb sensation, limb weakness, urinary retention, or bowel dysfunction.
• Careful neurological examination can localise compression levels; spinal tenderness on percussion may suggest vertebral involvement.
• Suspected cord compression requires emergency management with high-dose corticosteroids and urgent MRI evaluation.

Paraneoplastic Syndromes

• Although more common in small cell lung cancer, NSCLC can be associated with several paraneoplastic phenomena.
• Hypercalcaemia, most often seen in squamous cell carcinoma, may present with dehydration, confusion, or constipation.
• SIADH can cause hyponatraemia, leading to lethargy or confusion.
• Cushing syndrome (from ectopic ACTH secretion) may manifest with weight gain, proximal muscle weakness, and hypertension.
• Lambert-Eaton myasthenic syndrome can present with proximal lower limb weakness that improves with activity.
• Hypertrophic osteoarthropathy may cause joint pain and clubbing, commonly associated with adenocarcinoma.

Key Regional Manifestations of Metastatic Spread

Bone

• Commonly affects the axial skeleton and proximal long bones.
• May present with localised pain or pathological fractures.
• Vertebral involvement may produce symptoms of spinal cord compression.

Liver

• Often clinically silent until significant involvement.
• May present with hepatomegaly or right upper quadrant tenderness.

Adrenal Glands

• Usually asymptomatic; rarely presents with adrenal insufficiency.

Brain

• Affects up to 25% of patients.
• May cause headache, cognitive changes, seizures, vomiting, or focal deficits depending on the location of lesions.

Skin and Lymph Nodes

• Subcutaneous nodules and palpable lymphadenopathy (especially supraclavicular or cervical) may be the first sign of systemic spread.

Superior Sulcus (Pancoast) Tumours

• May present with a constellation of findings: shoulder pain, upper limb weakness, Horner’s syndrome, and rib or vertebral destruction.

Initial Imaging

Contrast-enhanced CT of the Chest, Neck, and Upper Abdomen

• Preferred first-line imaging in high-risk patients or those presenting with suspicious symptoms.
• Provides anatomical detail regarding the size, extent, and location of the primary tumour, as well as assessment of hilar, mediastinal lymph nodes, and potential distant spread (especially liver and adrenal glands).
• In cases of persistent haemoptysis or high clinical suspicion, a chest x-ray may be omitted in favour of direct CT imaging.
• CT has moderate sensitivity (60%) and specificity (80%) for mediastinal staging; therefore, abnormal findings typically require histologic confirmation.

Chest X-ray

• Though commonly ordered for initial evaluation of respiratory symptoms, it lacks sensitivity for early or small lesions.
• Used for monitoring known lesions, assessing response to treatment, or detecting post-procedural complications such as re-expansion after lung collapse.
• A normal x-ray does not exclude malignancy and must be followed by CT when clinical suspicion persists.

Advanced Imaging

FDG-PET/CT

• Plays a central role in staging by detecting both nodal involvement and distant metastases.
• Sensitivity and specificity for mediastinal staging typically range from 80–85% and ~90%, respectively.
• May detect occult disease not visible on CT alone and often alters stage and management plans.
• False positives can occur in infectious or inflammatory conditions; confirmation with biopsy is essential when PET identifies mediastinal disease.

MRI of Brain

• Recommended in patients with locally advanced disease, especially those considered for curative therapy or with neurological symptoms.
• More sensitive than CT in detecting small or asymptomatic brain metastases, which may alter treatment intent.

MRI of Thoracic Inlet

• Particularly useful in evaluating the local invasion of superior sulcus tumours.
• Helps assess resectability by identifying brachial plexus, subclavian vessel, and vertebral involvement.

Bone Scan

• Now largely supplanted by PET/CT for skeletal staging.
• May still be used in settings where PET is unavailable or when evaluating unexplained bone pain or elevated alkaline phosphatase.

Histological and Cytological Sampling

Bronchoscopy

• Ideal for central airway lesions, allowing direct visualisation and biopsy.
• High sensitivity (~90%) when sampling is combined with brushing, washing, or endobronchial ultrasound-guided needle aspiration.
• Autofluorescence or narrow band imaging can improve detection of pre-invasive lesions and may be used in surveillance post-treatment.

CT-guided Transthoracic Needle Biopsy

• Indicated for peripheral lung lesions not accessible via bronchoscopy.
• Provides material for cytology and molecular studies but has a higher false-negative rate (up to 26%) compared to central biopsies.

Sputum Cytology

• Non-invasive, low-cost test, particularly useful for centrally located tumours that exfoliate cells.
• High specificity but low sensitivity; not sufficient alone to exclude malignancy or determine histological subtype.

Thoracentesis and Pleural Biopsy

• Used in patients with pleural effusion to assess for malignant involvement.
• Ultrasound-guided aspiration is recommended to increase safety and diagnostic yield.
• If fluid cytology is negative, thoracoscopy should follow to directly visualise the pleura and obtain biopsies.

Mediastinal Lymph Node Assessment

Endobronchial Ultrasound (EBUS) and Endoscopic Ultrasound (EUS)

• Minimally invasive techniques for assessing mediastinal and hilar lymph nodes.
• Often used in combination to improve diagnostic yield and are now preferred over surgical staging in most cases.

Mediastinoscopy

• Considered the gold standard for mediastinal staging when non-invasive methods are inconclusive or negative despite high suspicion.
• Provides access to paratracheal and subcarinal lymph nodes.
• Sensitivity is approximately 80%, with a negative predictive value near 90%.

Video-Assisted Thoracoscopic Surgery (VATS)

• Used for diagnostic sampling of small peripheral lesions, pleural abnormalities, or inaccessible lymph nodes.
• Offers high sensitivity and specificity and can also aid in staging.

Laboratory Investigations

Full Blood Count (FBC)

• Evaluates baseline haematologic status before initiating systemic therapy.
• May reveal anaemia or, in immunosuppressed patients, neutropenia.

Liver Function Tests (LFTs)

• Elevations in hepatic enzymes may suggest liver metastases.
• Raised alkaline phosphatase may indicate osseous involvement.

Electrolytes and Renal Function

• Essential before chemotherapy or contrast-enhanced imaging.
• Hyponatraemia may point to SIADH, especially in small cell variants.

Serum Calcium

• Hypercalcaemia is often associated with squamous cell carcinoma, typically due to secretion of parathyroid hormone-related protein.

Pulmonary Function Testing (PFT)

• Required for patients undergoing surgery or radical radiotherapy.
• Includes spirometry, DLCO, and assessment of predicted postoperative values.
• Low-tech exercise tests or cardiopulmonary exercise testing may be used in marginal cases.

Cardiac Evaluation

• ECG is standard pre-operative assessment.
• Echocardiogram is performed in those with cardiac comorbidities or unexplained exercise limitation.

Molecular and Genetic Testing

EGFR, ALK, ROS1, and BRAF Mutations

• Guide selection of targeted therapies.
• EGFR mutations and ALK/ROS1 rearrangements are more common in never-smokers and adenocarcinomas.
• BRAF mutations are less common but have therapeutic implications, especially V600E.

• Determines eligibility for immune checkpoint inhibitors.
• Assessed on biopsy or cytology specimens; various assays are available.

RET, MET Exon 14, KRAS G12C, ERBB2 (HER2), and NTRK Fusions

• Identify subsets of NSCLC suitable for targeted treatments.
• Testing is recommended in advanced non-squamous NSCLC, particularly adenocarcinoma.

Staging Approach and Additional Workup

• Staging incorporates CT, PET/CT, brain MRI, mediastinal sampling, and biopsy results.
• TNM staging guides treatment intent and prognostication.
• PET/CT often alters staging and should precede surgical planning.
• Patients being considered for curative treatment require invasive nodal evaluation unless contraindicated.

Screening and Risk Stratification

• Low-dose CT is recommended annually for high-risk individuals (e.g., age 50–80, ≥20 pack-year smoking history, current or recent smokers).
• Screening has been shown to reduce lung cancer mortality by approximately 20%.
• Risk calculators may enhance candidate selection beyond traditional age and smoking thresholds.
• Overdiagnosis and false positives remain challenges, necessitating shared decision-making.

Small Cell Lung Cancer (SCLC)

• Typically presents as a centrally located mass with mediastinal invasion and bulky adenopathy.
• Symptoms include cough, haemoptysis, dyspnoea, chest pain, and systemic signs such as weight loss and facial swelling due to SVC compression.
• Paraneoplastic syndromes are more common than in NSCLC.
• CT reveals central mass and mediastinal lymphadenopathy; bronchoscopy with biopsy confirms diagnosis.

Metastatic Pulmonary Disease

• Can originate from breast, colon, renal, thyroid, melanoma, or sarcoma.
• Symptoms may be non-specific or reflect the primary site; pulmonary findings include nodules, masses, or diffuse infiltrates.
• CT chest shows multiple or solitary nodules, commonly in lower lobes.
• PET-CT and biopsy help determine origin; immunohistochemistry is often necessary.

Pulmonary Carcinoid Tumour

• Often presents with haemoptysis, cough, or recurrent pneumonia due to central airway obstruction.
• May be asymptomatic and incidentally detected.
• CT shows an enhancing endobronchial or peripheral nodule; bronchoscopy reveals pink, vascular lesions.

Pulmonary Tuberculosis

• Classically presents with chronic cough, haemoptysis, night sweats, weight loss, and fever.
• Chest x-ray or CT reveals upper lobe infiltrates, cavitation, or lymphadenopathy.
• Diagnosis confirmed by sputum AFB smear, culture, and nucleic acid amplification tests.

Organising Pneumonia

• Presents with persistent cough, malaise, dyspnoea, low-grade fever, and weight loss.
• CT shows patchy subpleural or peribronchial ground-glass opacities and consolidation.
• BAL and transbronchial biopsy support diagnosis; open biopsy may be required.

Sarcoidosis

• Multisystem granulomatous disease; pulmonary symptoms include dry cough and dyspnoea.
• CT shows bilateral hilar lymphadenopathy and upper lobe nodules.
• Biopsy reveals non-caseating granulomas; stains must exclude infectious causes.

Infectious Granulomas

• Caused by fungi (e.g., histoplasmosis, coccidioidomycosis) or mycobacteria.
• CT shows calcified nodules or lesions with halo signs.
• Travel history and exposure are essential; diagnosis supported by serology, culture, and biopsy.

Rheumatoid Nodules

• Found in patients with known rheumatoid arthritis; may mimic malignancy.
• CT shows cavitary nodules in upper lobes.
• Biopsy reveals central necrosis with palisading histiocytes and fibrinoid necrosis.

Granulomatosis with Polyangiitis

• Presents with cough, haemoptysis, chest pain, sinus symptoms, and systemic vasculitis.
• CT shows nodules, cavitations, and airway thickening.
• c-ANCA or PR3-ANCA typically positive; biopsy shows necrotising granulomatous inflammation.

Non-Hodgkin’s and Hodgkin’s Lymphoma

• Mediastinal masses may mimic lung cancer.
• Constitutional symptoms (fever, night sweats, weight loss) common.
• PET-CT shows FDG-avid masses; biopsy needed for definitive diagnosis.

Actinomycosis and Nocardiosis

• Mimic lung malignancy by invading adjacent tissues and crossing anatomical planes.
• Symptoms include fever, cough, and chest wall pain.
• Gram-positive organisms cultured from tissue or aspirates.

Amyloidosis

• Rare cause of lung nodules or tracheobronchial masses.
• CT may show calcified or non-calcified nodules.
• Diagnosis requires tissue biopsy with Congo red staining and serum/urine protein electrophoresis.

Hamartoma

• Benign tumour often detected incidentally.
• CT shows well-circumscribed nodule, commonly with fat and popcorn calcification.
• Rarely symptomatic unless endobronchial.

Bronchogenic Cyst

• Typically located in middle mediastinum.
• May cause cough, dysphagia, or chest pain.
• CT and MRI help characterise fluid-filled lesion.

Arteriovenous Malformation (AVM)

• May present with haemoptysis or dyspnoea.
• CT angiography shows direct communication between pulmonary artery and vein.
• Associated with hereditary haemorrhagic telangiectasia.

Thymoma or Thymic Carcinoma

• Often asymptomatic; may present with cough or paraneoplastic syndromes like myasthenia gravis.
• CT shows anterior mediastinal mass; PET-CT and biopsy guide diagnosis.

Germ Cell Tumours

• Common in young men; may present with anterior mediastinal mass.
• CT shows large, homogenous mass with soft tissue attenuation.
• Diagnosis supported by elevated AFP, β-hCG, and LDH.

Tracheal Tumours

• Present with cough, wheeze, stridor, or haemoptysis.
• Best visualised with CT or bronchoscopy.
• May be benign or malignant.

Thyroid Masses (e.g., Goitre, Thyroid Cancer)

• Anterior neck mass may compress the trachea or oesophagus.
• Symptoms include dysphagia, hoarseness, or dyspnoea.
• Thyroid function tests, ultrasound, and fine needle aspiration aid diagnosis.

Pneumonia and Post-obstructive Infections

• Acute or recurrent infiltrates may mimic neoplasm.
• Resolution with antibiotics suggests infection; lack of resolution warrants further imaging.

Pseudotumours (e.g., Mucoid Impaction)

• Radiologically mimic neoplastic lesions.
• Usually resolve with treatment of underlying bronchial obstruction.

Diagnostic Considerations

• NSCLC must be distinguished from SCLC and other mimickers to guide therapy.
• Confirming histology is essential to avoid misdiagnosis and inappropriate treatment.
• Overlapping clinical and radiologic features necessitate tissue sampling for definitive diagnosis.

General Principles

• Management is guided by disease stage, histological subtype, molecular profile, and patient fitness.
• Multidisciplinary team input is critical, including thoracic surgeons, medical and radiation oncologists, pulmonologists, radiologists, pathologists, and palliative care specialists.
• Early integration of supportive and palliative care has been shown to enhance both survival and quality of life.

Physical Activity

• Functional status, assessed by tools such as Karnofsky or Zubrod performance scales, is a strong prognostic factor.
• Patients should be encouraged to maintain physical activity during and after treatment to preserve function and reduce complications.
• A decline in activity may indicate disease progression or treatment-related toxicity and should prompt clinical reassessment.

Early-Stage NSCLC (Stage I–II)

Surgical Candidates

• Lobectomy is preferred, with pneumonectomy reserved for selected patients with sufficient pulmonary reserve.
• Limited resections (e.g., segmentectomy or wedge) are options for patients with poor functional status but carry higher recurrence risk.
• Video-assisted thoracoscopic surgery reduces morbidity and hospital stay.
• Routine mediastinal lymph node dissection is recommended.

Neoadjuvant Therapy

• For tumours ≥4 cm or node-positive disease, platinum-based chemotherapy with immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab, durvalumab) is favoured.
• Selection is based on PD-L1 status and presence of EGFR or ALK mutations.
• Chemoradiotherapy is reserved for immunotherapy-ineligible patients but carries a higher risk of perioperative complications.

Adjuvant Therapy

• Cisplatin-based chemotherapy improves survival in stage IIA–IIIB following complete resection.
• Targeted adjuvant options:
  • Osimertinib: EGFR exon 19 deletions or L858R mutations.
  • Alectinib: ALK-positive disease.
  • Atezolizumab, durvalumab, nivolumab, pembrolizumab: PD-L1 or immune profile dependent.

Postoperative Radiotherapy

• Considered in high-risk cases (e.g., positive margins, extracapsular nodal extension).
• Carries risks including radiation pneumonitis and oesophagitis.
• Prophylactic cranial irradiation is not recommended in NSCLC.

Non-Surgical Candidates

• Medically inoperable patients may be treated with stereotactic ablative radiotherapy (SABR), providing excellent local control.
• In highly selected patients, image-guided thermal ablation (e.g., radiofrequency, cryoablation) may be used.

Stage IIIA NSCLC

Surgical Candidates

• Surgery considered for non-bulky, single-zone N2 disease following neoadjuvant therapy.
• Neoadjuvant options include chemo-immunotherapy, chemotherapy alone, or chemoradiotherapy.
• Postoperative therapy depends on biomarker status and may include chemotherapy or targeted agents.

Unresectable Stage IIIA–C

• Concurrent chemoradiotherapy is preferred over sequential approaches in fit patients.
• Durvalumab: consolidation in PD-L1-positive cases post-chemoradiotherapy.
• Osimertinib: indicated for patients with EGFR exon 19 or L858R mutations post-treatment.

Advanced/Metastatic NSCLC (Stage IIIB–IV)

Molecular Testing

• Mandatory in all non-squamous NSCLC and selected squamous histologies.
• Actionable targets: EGFR, ALK, ROS1, BRAF, NTRK, MET exon 14, RET, KRAS G12C, HER2 (ERBB2), and PD-L1.

Targeted Therapies

• EGFR: Osimertinib preferred; alternatives include afatinib, erlotinib ± bevacizumab, or gefitinib.
• ALK: Alectinib, brigatinib, lorlatinib; ceritinib or crizotinib if needed.
• ROS1: Crizotinib, entrectinib, repotrectinib.
• BRAF V600E: Dabrafenib + trametinib, or encorafenib + binimetinib.
• MET exon 14: Capmatinib, tepotinib, or crizotinib.
• RET: Selpercatinib, pralsetinib.
• KRAS G12C: Sotorasib, adagrasib.
• HER2: Trastuzumab deruxtecan; trastuzumab emtansine as alternative.
• NTRK: Larotrectinib, entrectinib, repotrectinib.

Immunotherapy

• PD-L1 ≥50%: Pembrolizumab, atezolizumab, or cemiplimab monotherapy.
• PD-L1 1–49%: Pembrolizumab ± chemotherapy.
• PD-L1 <1%: Consider nivolumab + ipilimumab or combination chemo-immunotherapy.
• Durvalumab + tremelimumab + chemotherapy is suitable across PD-L1 ranges.

Systemic Chemotherapy

• Non-squamous: Platinum + pemetrexed; maintenance pemetrexed post-induction is standard.
• Squamous: Platinum + gemcitabine, paclitaxel, or docetaxel.
• Bevacizumab may be added in appropriate patients without haemoptysis or brain metastases.

Brain Metastases

• Options: Stereotactic radiosurgery, surgical resection, or whole-brain radiotherapy.
• TKIs with CNS penetration are preferred for patients with EGFR, ALK, ROS1, MET, or RET alterations.

Relapsed/Refractory NSCLC

• Immune checkpoint inhibitors (nivolumab, pembrolizumab, atezolizumab) offer improved survival post-chemotherapy.
• Cytotoxic agents (docetaxel, pemetrexed, paclitaxel) may be used alone or with bevacizumab/nintedanib.
• If a targetable mutation is discovered after first-line therapy, switch to the corresponding TKI (e.g., crizotinib for ALK).

Prevention of NSCLC

Smoking Cessation

• Key intervention to reduce incidence.
• Strategies include:
  • Public education.
  • Policy enforcement (taxation, public bans).
  • Supportive cessation tools (varenicline, bupropion, nicotine replacement).
• Combining pharmacological and behavioural therapies improves quit rates up to 35%.
• Risk of lung cancer declines gradually but other comorbidities improve earlier post-cessation.

Occupational/Environmental Measures

• Protective gear mandatory for workers exposed to asbestos or radioactive substances.
• Aspirin and NSAIDs may offer a chemopreventive effect, though evidence is not yet conclusive.

Screening

• Annual low-dose CT recommended for adults aged 50–80 with ≥20 pack-year smoking history, current smokers, or those who quit within the past 15 years.

Consultations

• Multidisciplinary consultations should include thoracic surgery, oncology (medical/radiation), pulmonology, and palliative care.
• Other specialties may be involved depending on metastases (e.g., neurology, orthopaedics, vascular surgery).

Long-Term Monitoring

• Surveillance:
  • H&P and chest CT every 6–12 months for the first 2–3 years, then annually.
  • Ongoing smoking cessation support.
• Vaccinations:
  • Annual influenza.
  • Pneumococcal and herpes zoster as per age and immune status.
• Lifestyle counselling:
  • Physical activity.
  • Balanced diet.
  • Psychosocial wellbeing and routine preventative care.

Determinants of Prognosis

• The most significant prognostic factors in NSCLC are the TNM (Tumour, Node, Metastasis) stage and the patient’s performance status.
• Poor functional status, assessed by tools such as the ECOG or Karnofsky scales, correlates with worse outcomes.
• Weight loss, anorexia, and other systemic symptoms like fatigue are independent markers of adverse prognosis.
• Lymphovascular invasion and occult lymph node metastases negatively impact survival, even in early stages.

Impact of Molecular and Imaging Markers

• The presence of actionable mutations can favourably influence prognosis. EGFR-activating mutations, more commonly seen in adenocarcinomas in never-smokers, females, and patients of East Asian descent, are associated with improved survival.
• High metabolic uptake (SUV) on PET scans is associated with poorer prognosis across stages I–IV.

Recurrence and Postoperative Outcomes

• After complete surgical resection, recurrence is observed in approximately 41% of patients.
• Median time to recurrence is around 11.5 months, and survival after recurrence is typically limited to a median of 8.1 months.
• Shorter post-recurrence survival correlates with poor pre-recurrence performance status, shorter disease-free intervals, distant metastatic relapse, and previous use of neoadjuvant chemotherapy or postoperative radiotherapy.

Survival Based on Staging

• Survival is generally higher when staging is based on pathological evaluation following surgical resection, compared to clinical staging from imaging alone.
• Surgical staging identifies occult lymph node involvement in up to 25% of patients initially thought to have stage I disease.
• Many patients with clinical stage I disease are upstaged after surgery, affecting prognosis assessments.

Five-Year Survival Estimates

Pathological (Surgical) Stage

• Stage IA1: 90%
• Stage IA2: 85%
• Stage IA3: 80%
• Stage IB: 73%
• Stage IIA: 65%
• Stage IIB: 56%
• Stage IIIA: 41%
• Stage IIIB: 24%
• Stage IIIC: 12%

Clinical (Imaging-Based) Stage

• Stage IA1: 92%
• Stage IA2: 83%
• Stage IA3: 77%
• Stage IB: 68%
• Stage IIA: 60%
• Stage IIB: 53%
• Stage IIIA: 36%
• Stage IIIB: 26%
• Stage IIIC: 13%
• Stage IVA: 10%
• Stage IVB: 0%

Other Prognostic Variables

• Male sex and increasing age are independently associated with worse survival.
• The ability to receive and complete standard therapies, such as surgery or concurrent chemoradiation, significantly affects long-term outcomes.

Malignant Pleural Effusion

• A common intrathoracic manifestation of metastatic spread.
• Causes dyspnoea and can lead to respiratory failure, particularly in patients with underlying cardiopulmonary comorbidities.
• Management includes thoracentesis, pleurodesis, or indwelling pleural catheters.

Post-Obstructive Pneumonia and Hypoxia

• Caused by large, centrally located tumours obstructing major airways.
• May present without classic signs such as fever or productive cough.
• Radiographic interpretation can be difficult due to tumour-related changes such as atelectasis.
• Requires urgent antibiotic therapy and airway relief via modalities like external beam radiotherapy, endobronchial brachytherapy, laser tumour debulking, stenting, photodynamic therapy, or surgical resection.
• Photodynamic therapy involves intravenous photosensitising agents and light activation via bronchoscopy to induce tumour cell death.
• Rapid intervention is essential in those with significant respiratory compromise.

Radiation-Induced Lung Fibrosis

• A common sequela of thoracic radiotherapy, usually asymptomatic but may lead to dyspnoea in patients with poor baseline lung function.
• High radiation doses increase risk of rare complications such as oesophageal stricture and bronchial stenosis.
• Preventive strategies include limiting radiation fields and using conformal planning techniques.

Superior Vena Cava Syndrome (SVCS)

• Occurs in approximately half of all malignant cases due to NSCLC.
• Results from external compression of the SVC, typically by bulky mediastinal adenopathy or right upper lobe tumours.
• Characterised by facial and upper extremity oedema, dyspnoea, orthopnoea, cough, facial plethora, and distended superficial veins.
• Although not often a medical emergency, rapid symptom onset may require urgent treatment.
• Management includes supplemental oxygen, head elevation, radiotherapy, chemotherapy, and in select cases, endovascular stenting for quicker relief.
• Surgery is rarely indicated.

Paraneoplastic Syndromes

• Occur in a subset of patients with NSCLC and reflect tumour secretion of biologically active substances.
• Common manifestations include:
  • Hypercalcaemia (due to PTHrP-like peptide)
  • SIADH
  • Cushing syndrome
  • Hypertrophic pulmonary osteoarthropathy
  • Clubbing
  • Trousseau syndrome (thromboembolic tendency)
• Management focuses on treating the underlying malignancy; additional supportive therapy is tailored to the specific syndrome.

Metastatic Complications

• Bone metastases: Cause pain, pathological fractures, and spinal cord compression.
• Brain metastases: Present with headaches, seizures, altered mental status, and focal neurological deficits.
• Spinal metastases: May lead to urgent neurological compromise requiring corticosteroids and radiotherapy.
• Hepatic metastases: Present with hepatomegaly, abdominal discomfort, or hepatic dysfunction.

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