Small Cell Lung Cancer and Paraneoplastic Syndromes
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Direct answer
Small cell lung cancer is a highly aggressive neuroendocrine carcinoma, strongly linked to smoking, that usually arises centrally and has disseminated by presentation. It responds initially to platinum-based chemotherapy and radiotherapy but relapses quickly. Its classic paraneoplastic syndromes are ectopic ACTH production causing Cushing syndrome, SIADH causing hyponatraemia, and Lambert-Eaton myasthenic syndrome, each of which shapes both diagnosis and management. Staging divides the disease into limited and extensive forms.
What you must remember
- Histology and site: neuroendocrine tumour arising in central bronchi, with chromogranin and synaptophysin positivity on immunohistochemistry.
- Staging: limited disease is confined to one hemithorax and one radiation field; extensive disease lies beyond that, and most patients are extensive at diagnosis.
- Ectopic ACTH: Cushing syndrome with hypokalaemia, metabolic alkalosis and marked pigmentation, with rapid onset and very high cortisol that may not suppress on dexamethasone.
- SIADH: hyponatraemia with inappropriately concentrated urine and low plasma osmolality; fluid restriction is first line, and sodium is corrected slowly to avoid osmotic demyelination.
- Lambert-Eaton syndrome: presynaptic voltage-gated calcium channel antibodies cause proximal limb weakness that improves with repeated effort, with reduced reflexes; treated with amifampridine and tumour treatment.
- Treatment: platinum with etoposide and thoracic radiotherapy for limited disease, prophylactic cranial irradiation in responders, and immunotherapy added to chemotherapy in extensive disease.
A 59-year-old smoker with sodium 122 and proximal weakness
A 59-year-old heavy smoker has a sodium of 122 mmol/L with low plasma osmolality and inappropriately concentrated urine, which fits SIADH. Chest CT shows a central hilar mass with mediastinal nodes, and bronchoscopic biopsy confirms small cell carcinoma.
- Restrict fluid: Fluid restriction is started for the hyponatraemia, and sodium is corrected by no more than about 8 to 10 mmol/L in 24 hours to avoid osmotic demyelination.
- Stage the disease: Staging includes CT of the abdomen, PET-CT and brain imaging, and the disease is classified as extensive if it extends beyond a single radiation field.
- Test for Lambert-Eaton: When proximal weakness is also present, Lambert-Eaton syndrome is tested for with antibodies and nerve conduction studies, since it strongly predicts this tumour.
- Treat the tumour: Chemotherapy with platinum and etoposide is the mainstay, with immunotherapy added in extensive disease and thoracic radiotherapy for limited disease.
- Consider ectopic ACTH: Ectopic ACTH production is considered in a patient with rapid-onset Cushing features and hypokalaemia, and it suggests a tumour rather than adrenal disease.
Where the examiner separates the paraneoplastic pairs
Paraneoplastic syndromes are tested as pairs that look alike on the surface.
- Trap: Confusing Lambert-Eaton syndrome with myasthenia gravis. Correct: Lambert-Eaton weakness improves with repeated effort and reflexes are reduced, with autonomic symptoms such as dry mouth and impotence, whereas myasthenia gravis worsens with exercise and reflexes are preserved.
- Trap: Dismissing Lambert-Eaton when no chest mass is seen. Correct: It is linked to small cell carcinoma, so a chest CT is needed even when the chest X-ray shows no mass.
- Trap: Correcting SIADH hyponatraemia too quickly. Correct: A rapid sodium rise carries a real risk of osmotic demyelination, and the examiner expects a stated limit.
- Trap: Attributing ectopic ACTH to pituitary Cushing disease. Correct: Ectopic ACTH is distinguished by high cortisol that usually fails to suppress on high-dose dexamethasone, which the examiner may test with a question stem.
Frequently asked questions
Which paraneoplastic syndromes are classic for small cell lung cancer?
Ectopic ACTH production, SIADH and Lambert-Eaton myasthenic syndrome are the classic paraneoplastic syndromes linked to small cell lung cancer. Ectopic ACTH typically presents with hypokalaemia and rapid-onset Cushing features.
How does Lambert-Eaton syndrome differ from myasthenia gravis?
In Lambert-Eaton syndrome, proximal limb weakness improves with repeated effort and reflexes are reduced, whereas myasthenia gravis worsens with exercise and reflexes are preserved. Lambert-Eaton is linked to presynaptic calcium channel antibodies and to small cell lung cancer.
How is hyponatraemia from SIADH treated?
Hyponatraemia from SIADH is treated first with fluid restriction and treatment of the underlying tumour, with sodium corrected slowly to avoid osmotic demyelination. Hypertonic saline is reserved for severe or symptomatic hyponatraemia.
What is the first-line chemotherapy for extensive small cell lung cancer?
Platinum with etoposide, combined with immunotherapy in extensive disease, is the standard first-line regimen. Thoracic radiotherapy is added in limited disease, with prophylactic cranial irradiation considered in responders.