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WHO Classification of Lung Tumours: Clinical Features, Morphology, and Diagnostic Approach

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1. WHO Classification of Lung Tumours (2021, 5th Edition)

Malignant Epithelial Tumours (WHO 2021)

Benign Lung Neoplasms (WHO)

• Neuroendocrine tumours are now grouped as one family spanning low-grade (carcinoids) through high-grade (SCLC, LCNEC)
• The term "bronchioloalveolar carcinoma (BAC)" is abolished; replaced by AIS and MIA
• SMARCA4-deficient tumours and NUT carcinoma added as new entities
• Greater integration of molecular biomarkers into classification

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2. Clinical Features of Lung Tumours

Epidemiology and Risk Factors

• Lung cancer accounts for ~45,000 new cases/year in the UK; 60% die within 1 year; only 15% survive 5 years
• Cigarette smoking is the dominant risk factor, accounting for 85-95% of all cases
• The risk is 60 times higher in heavy smokers (2 packs/day x 20 years) versus non-smokers
• Women are more susceptible to carcinogens in tobacco smoke than men
• Other risks: radon, asbestos, radioactive ore/chromium mining, atmospheric pollution
• About 10-15% of lung cancers occur in never-smokers, with EGFR mutations more common in this group (especially women, East Asian populations)

Intrathoracic Symptoms

• Cough (most common), which may be chronic and changing in character
• Haemoptysis - occurs in central tumours (squamous most common)
• Wheeze or stridor - from airway compression
• Dyspnoea - from atelectasis, effusion, or lymphangitic spread
• Post-obstructive pneumonia - recurrent or non-resolving pneumonia

• Hoarseness - recurrent laryngeal nerve palsy (left nerve more often, long intrathoracic course)
• Dysphagia - oesophageal compression
• Superior vena cava (SVC) syndrome - facial/arm oedema, venous distension, plethora; more common with SCLC and right-sided lesions
• Horner's syndrome - enophthalmos, ptosis, miosis, anhidrosis from cervical sympathetic plexus invasion
• Pancoast (superior sulcus) syndrome - apical tumour invading C8/T1/T2 nerves causing shoulder pain radiating in ulnar distribution + Horner's syndrome + rib destruction
• Phrenic nerve palsy - elevated hemidiaphragm
• Malignant pleural effusion - pain, dyspnoea
• Pericardial involvement - tamponade, arrhythmias

• Anorexia, weight loss (>10 lbs is a red-flag feature)
• Weakness, fever, night sweats

Extrathoracic Metastatic Disease

• 50% of squamous cell carcinoma

• 80% of adenocarcinoma and large cell carcinoma

• 95% of SCLC

Paraneoplastic Syndromes

• Lambert-Eaton myasthenic syndrome (LEMS) - autoantibodies against presynaptic voltage-gated calcium channels; proximal muscle weakness; associated with SCLC
• Hypertrophic pulmonary osteoarthropathy - periosteal new bone formation + clubbing of fingers; common with adenocarcinoma
• Peripheral neuropathy - purely sensory
• Acanthosis nigricans (dermatologic)
• Trousseau syndrome - hypercoagulable state with DVT/PE

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3. Morphology of Individual Lung Tumour Types

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3.1 Adenocarcinoma (Most Common Overall; ~40%)

• Adenocarcinoma in situ (AIS): ≤3 cm, pure lepidic growth, no stromal/vascular/pleural invasion. Formerly called bronchioloalveolar carcinoma (BAC)
• Minimally invasive adenocarcinoma (MIA): ≤3 cm lepidic-predominant tumour with ≤5 mm stromal invasion

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3.2 Squamous Cell Carcinoma (~25-30%)

• Keratinizing subtype: Keratin pearls (concentric whorls of keratinised cells), intercellular bridges (desmosomes), individual cell keratinisation - easily recognised
• Non-keratinizing subtype: No obvious keratinization; may have only subtle IHC evidence of squamous differentiation
• Basaloid subtype: Peripheral palisading of basal-type cells; high-grade; poor prognosis

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3.3 Small Cell Carcinoma (SCLC; ~15-20%)

• Small cells (~2-3x the size of a lymphocyte) with very scant cytoplasm
• Round-to-oval nuclei with finely granular "salt-and-pepper" chromatin
• Absent or inconspicuous nucleoli
• Nuclear moulding (cells mould around each other)
• Very high mitotic rate; extensive necrosis
• Azzopardi effect: Basophilic encrustation of vascular walls by DNA from necrotic tumour cells - characteristic
• Crushed cell artefact common in biopsies

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3.4 Large Cell Carcinoma (~10%)

• Sheets of large, polygonal, undifferentiated cells
• No gland formation, no squamous pearls, no neuroendocrine pattern on H&E
• Large nuclei with prominent nucleoli
• Diagnosis of exclusion after IHC work-up

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3.5 Large Cell Neuroendocrine Carcinoma (LCNEC)

• Organoid/trabecular/rosette architecture (neuroendocrine growth pattern) + large cell cytology
• IHC positive for neuroendocrine markers (CD56, synaptophysin, chromogranin)
• High mitotic rate (≥11/10 HPF); necrosis present
• Classified with high-grade neuroendocrine carcinomas alongside SCLC in WHO 2021

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3.6 Typical and Atypical Carcinoids

• Well-circumscribed, vascularised, reddish-brown intrabronchial polypoid mass
• Histology: uniform round-to-spindle cells, organoid/trabecular pattern, abundant granular cytoplasm, "salt-and-pepper" chromatin; <2 mitoses/2mm²; no necrosis
• Low-grade; 5-year survival >90% with resection

• 2-10 mitoses/2mm² OR punctate necrosis
• More aggressive than TC; intermediate prognosis

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3.7 Sarcomatoid Carcinoma

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4. Diagnostic Approach

Step 1: Clinical Suspicion and Imaging

• Smoking history (pack-years), haemoptysis, weight loss, chronic cough, Horner's syndrome, SVC syndrome

• First line; hilar mass, peripheral opacity, pleural effusion, mediastinal widening, cavitating lesion

• Mandatory for all suspected cases
• Characterises mass, lymph node status, chest wall/vascular invasion, pleural involvement
• Guides biopsy approach

• SUV >2.5 is highly suspicious for malignancy
• Best for mediastinal lymph node and extrathoracic staging
• False negatives in lesions <8mm, carcinoids, diabetes
• False positives in TB and sarcoidosis

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Step 2: Tissue Diagnosis

• Non-invasive; sensitivity ~40-60% for central tumours; lower for peripheral
• Positive findings: keratinised squamous cells with hyperchromatic nuclei (squamous carcinoma), adenocarcinoma cells with intracytoplasmic mucin vacuoles

• Flexible bronchoscopy with direct visualisation, brushings, washings, and transbronchial biopsy for central lesions
• Bronchoscopic biopsy: sensitivity ~70-80% for central endobronchial tumours

• EBUS-guided transbronchial needle aspiration (TBNA) of mediastinal/hilar lymph nodes
• Key tool for mediastinal staging AND diagnosis concurrently
• Rapid on-site evaluation (ROSE) improves diagnostic yield

• For peripheral lesions not accessible by bronchoscopy
• Core biopsy preferred over fine needle aspiration for molecular testing
• Pneumothorax is the main complication (~20-25%)

• For pleural-based lesions, evaluation of pleural effusion
• Pleuroscopy + biopsy for malignant effusion

• Provides definitive histological diagnosis AND curative treatment for resectable NSCLC
• Preferred margin assessment, lymph node staging

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Step 3: Pathological Evaluation (Histology + IHC)

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Step 4: Molecular/Biomarker Testing (Mandatory for NSCLC)

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Step 5: Staging (TNM - IASLC 8th Edition)

• T: Tumour size and local invasion
• N: Regional lymph node involvement (N0-N3)
• M: Distant metastases

• CT thorax/abdomen/pelvis
• PET-CT (preferred over CT alone for nodal and extrathoracic staging)
• MRI brain for SCLC (and NSCLC stage III/IV)
• EBUS ± mediastinoscopy for lymph node sampling when CT/PET show suspicious nodes

• Limited stage: confined to one hemithorax + ipsilateral nodes (within a radiotherapy portal)
• Extensive stage: beyond the above; ~two-thirds of patients at presentation

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Summary Points

1. Adenocarcinoma is now the most common lung cancer overall, including in women and non-smokers.
2. The WHO 2021 classification groups neuroendocrine tumours as a spectrum (carcinoids → LCNEC → SCLC) and abolishes the term "bronchioloalveolar carcinoma."
3. SCLC and NSCLC are the primary clinical divide because they differ in treatment strategy, prognosis, and biology.
4. Paraneoplastic syndromes (SIADH, Cushing, hypercalcaemia, LEMS) may be the presenting feature.
5. Pancoast syndrome and SVC syndrome are important patterns of regional spread.
6. The diagnostic approach integrates imaging, tissue biopsy, IHC, and mandatory molecular testing for NSCLC.
7. NGS-based molecular profiling now drives treatment selection in metastatic NSCLC.

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• Robbins, Cotran & Kumar Pathologic Basis of Disease (pp. 671-768)
• Robbins & Kumar Basic Pathology - Table 11.5, WHO classification 2021
• Harrison's Principles of Internal Medicine, 22e (pp. 659-670)
• Murray & Nadel's Textbook of Respiratory Medicine - Chapter 22 (WHO 2015 classification)
• Bailey & Love's Short Practice of Surgery, 28e (pp. 1006-1010)
• Mulholland & Greenfield's Surgery, 7e - Tables 79.1, 79.2
• Nicholson AG et al. The 2021 WHO Classification of Lung Tumors - J Thorac Oncol 2022 (PMID: 34808341)