Paraneoplastic syndromes

Definition. Remote, non-metastatic effects of malignancy mediated by tumour-secreted hormones, cytokines or cross-reacting onconeural antibodies — not by tumour mass, local invasion or metastasis. They are important because they are frequently the first presentation of an occult cancer in an older adult.

Endocrine syndromes. SIADH with hyponatraemia (small cell lung cancer); ectopic ACTH (SCLC, carcinoid) causing hypokalaemic alkalosis, hyperglycaemia and proximal myopathy rather than classic Cushingoid habitus; humoral hypercalcaemia of malignancy from PTHrP (squamous cell lung, renal and breast cancer); and hypoglycaemia from IGF-2 (hepatoma, sarcoma).

Neurological syndromes. Lambert-Eaton myasthenic syndrome (SCLC) — proximal weakness that improves with exercise, autonomic features and absent reflexes, with anti-VGCC antibodies; paraneoplastic cerebellar degeneration (anti-Yo in ovarian and breast cancer, anti-Hu in SCLC); limbic encephalitis (anti-Hu, anti-Ma2); sensory neuronopathy; and opsoclonus-myoclonus.

Haematological and vascular syndromes. Anaemia of chronic disease, erythrocytosis from ectopic erythropoietin (renal cell carcinoma, hepatoma, cerebellar haemangioblastoma), thrombocytosis, leukaemoid reaction, eosinophilia, migratory thrombophlebitis — Trousseau's sign, classically pancreatic carcinoma, non-bacterial thrombotic endocarditis and DIC.

Dermatological and rheumatological syndromes. Acanthosis nigricans (gastric adenocarcinoma), dermatomyositis with heliotrope rash and Gottron's papules, Leser-Trélat sign (sudden eruptive seborrhoeic keratoses), acquired ichthyosis, hypertrophic pulmonary osteoarthropathy with clubbing (lung cancer), paraneoplastic pemphigus and palmar fasciitis.

Approach and management. Recognise the syndrome, then search for the underlying tumour (CT chest-abdomen-pelvis, mammography, PET-CT, antibody-directed screening). Treating the tumour is the definitive treatment. Symptomatic measures: fluid restriction or tolvaptan for SIADH; hydration plus zoledronate for hypercalcaemia; and immunotherapy (corticosteroids, IVIG, plasma exchange, rituximab) for antibody-mediated neurological syndromes — though response is often poor once neuronal loss has occurred, so early recognition is critical.

PNS-Care diagnostic framework (Graus et al., updated criteria now in general use) classifies paraneoplastic neurological syndromes as definite, probable or possible using the clinical phenotype, the antibody type (high-risk antibodies such as anti-Hu, anti-Yo and anti-Ma2 versus intermediate-risk antibodies) and the presence of tumour. A parallel development is the growing recognition of immune checkpoint inhibitor-triggered paraneoplastic neurological syndromes, increasingly seen as immunotherapy use expands in older patients with cancer.