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Lung Tumours: Clinical Features, Morphology, and Diagnostic Approach

Overview and Classification

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1. Adenocarcinoma

Clinical Features

• Most common subtype overall; more prevalent in women and non-smokers
• Typically peripheral in location
• Often presents as a solitary pulmonary nodule or ground-glass opacity on CT
• May be asymptomatic until late (peripheral lesions avoid early bronchial obstruction)
• Paraneoplastic: migratory thrombophlebitis (Trousseau syndrome), non-bacterial endocarditis, DIC, hypercoagulability

Morphology

• Gross: Peripheral grey-white mass, often with central scarring + pleural puckering (arrow sign on CT/gross specimen); anthracotic pigment incorporation
• Microscopic: Gland-forming architecture (acinar, papillary, lepidic, micropapillary patterns); mucin production present; abundant cytoplasm, pleomorphic nuclei with coarse chromatin and prominent nucleoli
• Precursor lesions: Atypical adenomatous hyperplasia (AAH) → Adenocarcinoma in situ (AIS) → Minimally invasive → Invasive adenocarcinoma
• IHC: TTF-1 positive (nuclear staining - see inset in image below), CK7+, mucin+, napsin-A+

Key Molecular Targets

• EGFR mutations (~20% of adenocarcinomas; enriched in non-smokers, women, East Asians) - targetable with erlotinib/osimertinib
• ALK fusions (4-6%; non-smokers, often signet-ring morphology) - targetable with crizotinib/alectinib
• KRAS mutations (~30%; associated with smoking)
• BRAF, ROS1, MET - additional actionable targets

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2. Squamous Cell Carcinoma

Clinical Features

• Strongly associated with heavy smoking
• Typically central/hilar in location - arises from main/lobar bronchi
• Presents with: cough, haemoptysis, post-obstructive pneumonia, atelectasis
• Cavitation is common (central necrosis)
• Paraneoplastic: Hypercalcaemia (via PTHrP secretion) - most characteristic
• Pancoast tumour (superior sulcus): shoulder/arm pain, Horner syndrome

Morphology

• Gross: Central grey-white hilar mass invading bronchial wall and adjacent parenchyma; may cavitate
• Microscopic: Squamous differentiation - keratin pearls, individual cell keratinisation, intercellular bridges (desmosomes); pleomorphic nuclei
• Precursor lesions: Squamous metaplasia → Dysplasia → Squamous cell carcinoma in situ → Invasive
• IHC: p40/p63 positive, CK5/6+, TTF-1 negative, mucin negative

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3. Small Cell Lung Carcinoma (SCLC)

Clinical Features

• Almost always in heavy smokers (diagnosis should be reconsidered in non-smokers)
• Central origin, rapid growth, invariably metastatic at diagnosis
• Mediastinal extension causes: SVC syndrome, recurrent laryngeal nerve palsy, dysphagia
• Pulmonary symptoms: cough, wheeze, dyspnoea, haemoptysis
• Widespread metastases: liver, brain, bone, adrenal glands
• Paraneoplastic syndromes are common and distinctive:
  • SIADH (ectopic ADH)
  • Eaton-Lambert syndrome (anti-VGCC antibodies - proximal weakness, improves with repeated use)
  • Ectopic ACTH/Cushing syndrome (ectopic ACTH)
  • Gastrin-releasing peptide, calcitonin production

Morphology

• Gross: Large central mass, often with necrosis; white-grey, soft consistency
• Microscopic (2021 WHO definition):
  • Small cells with scant cytoplasm
  • Finely granular "salt and pepper" nuclear chromatin - hyperchromatic
  • Absent or inconspicuous nucleoli
  • Cell size typically < 3 resting lymphocytes diameter (though variable)
  • Nuclear moulding prominent
  • Azzopardi effect: basophilic DNA encrustation of vessel walls from necrotic tumour cells
  • High mitotic rate: >60 mitoses per 2 mm²
  • Extensive necrosis and apoptosis

• IHC: Neuroendocrine markers - CD56, synaptophysin, chromogranin positive; dense-core granules on electron microscopy; TTF-1 often positive; EMA/CK positive; mucin absent

Staging

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4. Large Cell Carcinoma

Clinical Features

• Diagnosis of exclusion - no glandular, squamous, or neuroendocrine differentiation by light microscopy
• Typically peripheral; presents late
• Poor prognosis

Morphology

• Microscopic: Sheets of large pleomorphic cells; abundant cytoplasm; vesicular nuclei with prominent nucleoli; no keratin pearls, gland formation, or neuroendocrine architecture by H&E
• Large cell neuroendocrine carcinoma (LCNEC): defined as high-grade NSCLC with neuroendocrine morphology (organoid nesting, trabecular, rosette-like, palisading patterns) + positive neuroendocrine IHC (CD56, chromogranin, synaptophysin); >10 mitoses/2 mm²; cells are relatively large with moderate-to-abundant cytoplasm; nucleoli prominent (key distinction from SCLC)

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5. Carcinoid Tumours (Neuroendocrine)

Clinical Features

• Occur in younger adults (mean ~40 years); represent ~5% of pulmonary neoplasms
• May be part of MEN syndrome
• Typical carcinoid: low-grade; 5-15% metastasize to hilar nodes; distant metastases rare; often curable by resection
• Atypical carcinoid: higher mitotic rate, higher lymph node and distant metastasis risk; TP53 mutations in 20-40%
• Carcinoid syndrome (flushing, diarrhoea) if metastatic

Morphology

• Arise in main bronchi; two patterns:
  1. Polypoid spherical intraluminal mass
  2. Mucosal plaque penetrating bronchial wall (collar-button lesion)
• Microscopic: Nests of uniform cells; regular round nuclei; "salt-and-pepper" chromatin; absent or rare mitoses; little pleomorphism
• Spectrum: Typical carcinoid → Atypical carcinoid → LCNEC → SCLC (increasing aggressiveness)

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Comparison: SCLC vs NSCLC

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Paraneoplastic Syndromes Summary

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Diagnostic Approach

1. Imaging

• CT chest (with contrast): First-line; characterise mass (size, location, density, cavitation, lymphadenopathy); guide biopsy
• PET-CT (FDG): Avid uptake in most lung cancers due to high metabolic rate; essential for staging NSCLC; identifies unsuspected metastases; guides biopsy to most metabolically active area; changes management in significant proportion of patients
  • SCLC: PET-CT changes staging (LD vs. ED) in ~15% of cases
• Brain MRI: Staging for SCLC and high-stage NSCLC
• Bone scan / MRI spine: Bone metastases

2. Tissue Diagnosis

• Bronchoscopy + BAL, brushings, endobronchial biopsy: Central tumours (squamous cell, SCLC)
• CT-guided percutaneous needle biopsy: Peripheral lesions; FDG-PET guidance targets most active area
• EBUS (Endobronchial ultrasound-guided TBNA): Mediastinal/hilar lymph nodes - staging
• Sputum cytology: Sensitivity limited; useful if central tumour with endobronchial involvement
• Thoracentesis: Malignant pleural effusion (cytology of fluid)
• Liquid biopsy (plasma ctDNA): EGFR mutation detection when tissue inadequate

3. Pathological/Histological Workup

• H&E morphology: Initial classification (SCLC vs NSCLC; glandular vs squamous vs undifferentiated)
• Immunohistochemistry panel:
  • Adenocarcinoma: TTF-1+, napsin-A+, CK7+
  • Squamous: p40/p63+, CK5/6+, TTF-1-
  • SCLC/Neuroendocrine: CD56+, synaptophysin+, chromogranin+; high Ki-67
  • LCNEC: neuroendocrine morphology + IHC markers

4. Molecular/Biomarker Testing (NSCLC - mandatory before treatment)

• EGFR mutation (exons 18-21, esp. exon 19 del and exon 21 L858R)
• ALK rearrangement (FISH, IHC, NGS)
• ROS1 rearrangement
• KRAS G12C mutation (targetable with sotorasib)
• BRAF V600E
• MET exon 14 skipping / amplification
• NTRK fusions
• PD-L1 expression (IHC): Predicts response to checkpoint inhibitors (pembrolizumab, atezolizumab); even PD-L1-negative tumours may respond via tumour microenvironment macrophages
• Tumour mutation burden (TMB): High TMB correlates with immunotherapy response

5. Laboratory Tests

• FBC, LFTs, renal function, LDH (staging/baseline)
• Serum calcium (PTHrP-mediated hypercalcaemia in squamous)
• Serum sodium (SIADH in SCLC)
• α1-antitrypsin (if concurrent emphysema)

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Staging

• NSCLC: TNM staging (IASLC 8th edition) - Stage I-IV; drives surgical vs. chemo-radiation vs. systemic therapy decisions
• SCLC: Traditionally Limited disease (LD) vs Extensive disease (ED); IASLC now recommends TNM staging as well

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• Adenocarcinoma is the most common lung cancer overall, especially in non-smokers and women
• Squamous cell carcinoma is central, cavitates, causes hypercalcaemia
• SCLC is central, always treated with chemotherapy (not surgery), has paraneoplastic syndromes, and invariably recurs despite initial response
• All NSCLC patients require molecular profiling before starting systemic treatment
• PET-CT is essential for staging and identifies occult metastases that change management
• SCLC has the highest mutation burden of any lung cancer but is paradoxically less responsive to checkpoint inhibitors than NSCLC