Endocrine syndromes associated with malignancy
Description
- Hormone or hormone-like secretion by tumour cells, or an immune reaction to them, producing a syndrome remote from the tumour and its metastases
- *May precede the cancer diagnosis by months, and may recur before radiological relapse*
- Severity does not track tumour bulk
Epidemiology
- Clinically significant paraneoplastic endocrine syndromes in ~1-10% of cancers
- Small cell lung cancer is the dominant cause - SIADH, ectopic ACTH, LEMS, anti-Hu syndromes
- Hypercalcaemia is the commonest overall (20-30% of all cancer patients at some point)
Aetiopathogenesis
The high-yield syndromes
| Syndrome | Mediator | Classic tumours |
|---|---|---|
| SIADH | ADH (vasopressin) | SCLC (~10-15%), also head and neck SCC, mesothelioma, lymphoma |
| Humoral hypercalcaemia | PTHrP | Squamous cell (lung, head and neck, oesophagus), renal cell, breast, ovarian, HTLV-1 ATLL |
| Hypercalcaemia | 1,25-(OH)2 vitamin D | Lymphoma (Hodgkin and NHL) |
| Hypercalcaemia | Local osteolysis (IL-1, RANKL) | Myeloma, breast |
| Ectopic ACTH / Cushing's | ACTH (and CRH) | SCLC, bronchial and thymic carcinoid, medullary thyroid, phaeochromocytoma, pancreatic NET |
| Non-islet cell tumour hypoglycaemia | "Big" IGF-2 | Large mesenchymal tumours (fibrosarcoma, solitary fibrous tumour of pleura), hepatocellular Ca, adrenocortical Ca |
| Hyperthyroidism | beta-hCG cross-reacting at the TSH receptor | Gestational trophoblastic disease, germ cell tumour, struma ovarii |
| Acromegaly | Ectopic GHRH (rarely GH) | Bronchial and pancreatic NET |
| Gynaecomastia | beta-hCG | Germ cell tumour, hepatocellular, lung |
| Carcinoid syndrome | Serotonin, tachykinins | Midgut NET with liver metastases (or bronchial/ovarian NET without) |
| Erythrocytosis | EPO | Renal cell, hepatocellular, cerebellar haemangioblastoma, uterine leiomyoma |
| Hypophosphataemic osteomalacia | FGF23 | Phosphaturic mesenchymal tumour |
SIADH - the one to know cold
- Euvolaemic hypotonic hyponatraemia
- dec serum osmolality (<275), inappropriately concentrated urine (osmolality >100), urine Na >30-40 mmol/L
- Normal thyroid, adrenal and renal function; not on diuretics
- Presents with confusion, nausea, headache, falls, seizures; chronicity determines severity
- Also caused by drugs (SSRIs, carbamazepine, cyclophosphamide, vincristine, cisplatin), pain, nausea, CNS and pulmonary disease - the malignancy is only one candidate
Ectopic ACTH vs pituitary Cushing's
| Ectopic ACTH | Pituitary (Cushing's disease) | |
|---|---|---|
| Onset | Rapid weeks-months | Insidious years |
| Phenotype | Weight loss, weakness, pigmentation rather than classic cushingoid habitus | Classic habitus |
| Hypokalaemic alkalosis | Severe (cortisol overwhelms 11-beta-HSD2 -> mineralocorticoid effect) | Mild |
| ACTH level | Very high | Moderately high |
| High-dose dexamethasone suppression | No suppression | Suppresses |
| CRH stimulation | No response | Responds |
| Petrosal sinus sampling | No central-to-peripheral gradient | Gradient present |
Diagnosis
- Think of it when the biochemistry does not fit the clinical picture - hyponatraemia in a well patient, hypokalaemia with alkalosis and pigmentation, recurrent hypoglycaemia with a suppressed insulin
- Confirm the biochemical syndrome first, then hunt the tumour
- Investigations by syndrome
- SIADH: paired serum and urine osmolality and sodium, TSH and morning cortisol to exclude the mimics
- Hypercalcaemia: PTH (suppressed), PTHrP, 1,25-(OH)2 vitamin D, phosphate, ALP
- Ectopic ACTH: 24h urinary free cortisol/late-night salivary cortisol, ACTH, high-dose dexamethasone suppression, inferior petrosal sinus sampling, CT chest and 68Ga-DOTATATE PET
- Hypoglycaemia: insulin, C-peptide (both suppressed), IGF-2:IGF-1 ratio raised
- Carcinoid: 24h urinary 5-HIAA, chromogranin A, DOTATATE PET, echocardiogram for right-sided valve disease
- CT chest/abdomen/pelvis; FDG PET for occult malignancy; DOTATATE PET for neuroendocrine sources
Management
The principle
- *Treating the tumour is the definitive treatment* - the syndrome resolves with response and recurs with relapse
- Meanwhile, treat the endocrine abnormality on its own merits
SIADH
- Fluid restriction 800-1000 mL/day first line
- Hypertonic 3% saline for seizures or severe symptomatic hyponatraemia
- *Correct by no more than 8-10 mmol/L in 24 hours* - osmotic demyelination
- Second line: tolvaptan (vaptan), demeclocycline, oral salt/urea
- Treat the SCLC - sodium usually normalises within 1-2 cycles
Hypercalcaemia
- IV 0.9% saline, then zoledronic acid (or denosumab if renal impairment or bisphosphonate-refractory)
- Corticosteroids only for the 1,25-vitamin D mediated (lymphoma/granulomatous) form
- Calcitonin as a bridge
Ectopic ACTH
- *A medical emergency - profound hypokalaemia, hyperglycaemia, hypertension, psychosis and opportunistic infection*
- Steroidogenesis inhibitors: metyrapone, ketoconazole, osilodrostat (or etomidate infusion if critically unwell)
- PJP prophylaxis, potassium replacement, spironolactone, glycaemic control, VTE prophylaxis
- Bilateral adrenalectomy if refractory and prognosis permits
Others
- IGF-2 hypoglycaemia: dextrose infusion, glucocorticoids, GH; resect the tumour if possible
- Carcinoid: octreotide/lanreotide; octreotide cover before anaesthesia or embolisation to prevent carcinoid crisis
- hCG-mediated thyrotoxicosis: beta-blocker, treat the tumour
Associations
- Small cell lung cancer - SIADH, ectopic ACTH, LEMS, anti-Hu encephalomyelitis/subacute sensory neuronopathy, cerebellar degeneration
- Squamous cell carcinoma - PTHrP hypercalcaemia, hypertrophic pulmonary osteoarthropathy
- Renal cell carcinoma - EPO polycythaemia, hypercalcaemia, hypertension (renin), Stauffer's syndrome
- Lymphoma - 1,25-vitamin D hypercalcaemia
- Thymoma - myasthenia gravis, red cell aplasia, hypogammaglobulinaemia
- Neuroendocrine tumours - carcinoid syndrome, ectopic GHRH, insulin, gastrin, VIP, glucagon
- Non-endocrine paraneoplastic syndromes worth knowing alongside: dermatomyositis (ovarian, nasopharyngeal, lung), acanthosis nigricans (gastric), Trousseau's migratory thrombophlebitis (pancreas), membranous nephropathy (solid tumours), anti-NMDA receptor encephalitis (ovarian teratoma)
Natural history & complications
- Parallels the tumour - improves with response, recurs with relapse
- *A rising sodium requirement or recurrent hypercalcaemia can herald relapse before imaging does*
- Ectopic ACTH carries the worst prognosis of the paraneoplastic endocrine syndromes - median survival often <12 months, and death is frequently from infection or metabolic complications rather than tumour bulk
- SIADH from SCLC generally resolves with chemotherapy; persistence suggests refractory disease
- Hypercalcaemia of malignancy historically indicated a median survival of 3-4 months - still a poor prognostic marker
- Neurological paraneoplastic syndromes are the exception - antibody-mediated damage is often irreversible even when the tumour is cured
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