Tutorial 10: Lung Cancer

Lung cancer is the leading cause of cancer death worldwide. Approximately 80% of cases occur in current or former smokers, though only 10–15% of heavy smokers develop cancer, indicating that individual genetic susceptibility — particularly polymorphisms in liver enzymes that metabolise procarcinogens — modifies risk. Asbestos exposure synergistically increases the risk of lung cancer in smokers beyond the simple additive effect of the two individual risk factors.

Lung cancer is the result of accumulated genetic mutations in bronchial epithelial cells under the influence of chemical carcinogens in cigarette smoke. Mutations occur in proto-oncogenes (EGFR, KRAS) and tumour suppressor genes (TP53, RB1), with different mutation profiles characterising different histological types.

Adenocarcinoma (38% of lung cancers) is a tumour that forms glands and may produce mucin. It is the most common type in non-smokers and is more common in women. Gain-of-function mutations in EGFR (present in ~15% of Western cases, ~50% of Asian non-smokers) and KRAS are the key driver mutations. Adenocarcinomas are typically peripheral, arising under the pleura. Lepidic growth — tumour cells growing along pre-existing alveolar walls without stromal invasion — is a well-differentiated pattern specific to lung adenocarcinoma.

Squamous cell carcinoma (SCC, 20%) is strongly associated with smoking. Loss-of-function mutations in TP53 are the hallmark. SCC arises centrally from bronchial epithelium that has undergone squamous metaplasia (bronchial pseudostratified columnar epithelium replaced by squamous epithelium as a response to smoke), then dysplasia, before invasive carcinoma develops — making it the type with the clearest defined premalignant sequence. Histologically: keratin pearls (whorls of cells with central keratinisation) and intercellular bridges distinguish well-differentiated SCC.

Small cell carcinoma (SCLC, 14%) has the strongest association with smoking. It arises from neuroendocrine cells of the bronchial epithelium ("Kulchitsky cells"), making it part of the broader group of neuroendocrine tumours. Histologically: small cells with very little cytoplasm, hyperchromatic nuclei with finely granular chromatin, and nuclear moulding (adjacent nuclei conform to each other's shape, like puzzle pieces). SCLC is highly malignant and almost always metastatic at presentation, making surgery inappropriate in the vast majority of cases. It is highly chemosensitive and radiosensitive (unlike other lung cancer types). Key mutations: TP53 and BCL2 anti-apoptotic gene.

Paraneoplastic syndromes occur in approximately 10% of cancer patients. SCLC is particularly associated with ectopic hormone production: ADH (SIADH → hyponatraemia), ACTH (Cushing's syndrome → hypokalaemia, hypertension, hyperglycaemia, proximal myopathy), and PTHrP (hypercalcaemia) — though PTHrP is more often produced by SCC. Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune paraneoplastic complication of SCLC in which anti-VGCC (voltage-gated calcium channel) antibodies impair presynaptic ACh release at the neuromuscular junction, causing proximal muscle weakness that paradoxically improves with repeated contraction (unlike myasthenia gravis).

Treatment: adenocarcinomas and SCCs with operable disease are treated with surgical resection (lobectomy); targeted therapies against EGFR (erlotinib, osimertinib) and ALK (crizotinib) are used for specific molecular subtypes. SCLC is treated with platinum-based chemotherapy + etoposide, with immunotherapy (atezolizumab) for extensive-stage disease. Despite improvements, 5-year survival for all lung cancer is approximately 16%.