What are paraneoplastic syndromes and why do they matter?
Paraneoplastic syndromes are systemic manifestations of a malignancy that are not due to direct tumour invasion or metastasis. Instead, tumour cells produce hormones, peptides, cytokines or autoantibodies that act on distant organs — endocrine, neurological, dermatological, haematological, renal and others. They occur in up to 8% of cancer patients.
Their importance is diagnostic: symptoms can appear before the cancer is known, so recognising the syndrome can lead to an early diagnosis of an occult tumour. They are most common with lung cancer (especially small cell), breast cancer, gynaecological and haematological malignancies.
| Mechanism | How it works | Examples |
|---|---|---|
| Ectopic hormone / peptide secretion | Tumour secretes a hormone not normally made by that tissue | ADH (SIADH), ACTH (Cushing), PTHrP (hypercalcaemia), erythropoietin, big IGF-II |
| Immune cross-reaction | Antibodies or T cells against tumour antigens also attack normal tissue sharing the antigen (onconeural antigens) | Anti-Yo cerebellar degeneration, anti-Hu encephalomyelitis, anti-VGCC Lambert-Eaton |
Which tumour causes which paraneoplastic syndrome?
This master table is the single most tested part of the topic. Learn it as tumour ↔ product ↔ syndrome.
| Syndrome | Mediator | Classic tumour(s) |
|---|---|---|
| SIADH (hyponatraemia) | Ectopic ADH | Small cell lung cancer |
| Cushing syndrome | Ectopic ACTH | Small cell lung cancer, bronchial carcinoid |
| Hypercalcaemia (humoral) | PTHrP | Squamous cell carcinoma of lung, head and neck; breast, ovarian, renal cancer |
| Hypercalcaemia | 1,25-dihydroxy vitamin D (calcitriol) | Hodgkin lymphoma (almost all cases), about one-third of non-Hodgkin lymphoma |
| Polycythaemia | Erythropoietin | Renal cell carcinoma, hepatocellular carcinoma, cerebellar haemangioma, uterine myoma |
| Hypoglycaemia (non-islet cell) | Big IGF-II | Fibrosarcoma and other mesenchymal sarcomas, hepatocellular carcinoma |
| Carcinoid syndrome | Serotonin, bradykinin | Carcinoid-type bronchial adenoma; pancreatic and gastric carcinoma |
| Lambert-Eaton syndrome | Anti-VGCC antibodies | Small cell lung cancer |
| Cerebellar degeneration | Anti-Yo (PCA-1), anti-Hu, anti-VGCC | Ovarian and breast cancer (anti-Yo); SCLC; Hodgkin lymphoma |
| Myasthenia gravis | Autoantibodies at the neuromuscular junction | Thymoma |
| Acanthosis nigricans (malignant) | TGF (growth factors) | Gastric adenocarcinoma |
| Sign of Leser-Trélat | — | Gastric adenocarcinoma and other GI adenocarcinomas |
| Trousseau syndrome (migratory thrombophlebitis) | Procoagulants | Pancreatic and bronchogenic carcinoma |
| Hypertrophic osteoarthropathy | — | Digital clubbing, joint swelling and pain; may resolve with cancer treatment |
What are the endocrine paraneoplastic syndromes?
SIADH is seen most often with small cell lung cancer (SCLC), which arises from neuroendocrine cells of the bronchus. Hyponatraemia presents with confusion, nausea and headache, and is an adverse prognostic factor in SCLC.
Ectopic ACTH syndrome produces ACTH-dependent Cushing syndrome. Its two commonest sources are bronchial carcinoid and small cell lung cancer — the first a well-differentiated tumour with a good prognosis when it can be removed surgically, the second a poorly differentiated tumour with a very poor prognosis. A high-dose dexamethasone test helps separate a pituitary from an ectopic source.
| Mechanism | Share / tumours | Note |
|---|---|---|
| PTHrP secretion (humoral hypercalcaemia of malignancy) | About 80% of cases; squamous cell carcinoma of head, neck and lung; breast, ovarian, renal | Needs no bone metastasis |
| Osteolytic bone metastases | Multiple myeloma; solid tumours such as breast cancer that spread to bone | Local release of osteoclast-activating factors |
| Calcitriol production | Hodgkin lymphoma, about one-third of non-Hodgkin lymphoma, granulomatous diseases | Responds to glucocorticoids |
Paraneoplastic hypercalcaemia carries a grim prognosis — in one study the 30-day inpatient mortality was 50%. Non-islet cell tumour hypoglycaemia (Doege-Potter syndrome) can drop glucose as low as 20 mg/dL; it is caused by an insulin-like substance, big IGF-II.
Which neurological paraneoplastic syndromes are tested — LEMS and anti-Yo?
Neurological syndromes are caused by onconeural antibodies — for example ANNA-1 (anti-Hu), ANNA-2, PCA-1 (anti-Yo), CRMP-5, anti-amphiphysin and anti-recoverin — raised against tumour antigens that are also expressed by neurons.
| Syndrome | Features | Antibody / tumour |
|---|---|---|
| Subacute cerebellar degeneration | Ataxia, dysarthria, dysphagia, diplopia, vertigo, nausea | Anti-Yo (PCA-1) — ovarian and breast cancer; anti-Hu or anti-VGCC — SCLC; Hodgkin lymphoma |
| Encephalomyelitis / limbic encephalitis | Cerebellar, brainstem, limbic and spinal cord inflammation | Anti-Hu — SCLC |
| Opsoclonus-myoclonus | Chaotic eye movements, body jerks, ataxia; opsoclonus prominent in children under 4 | Paediatric and adult tumours |
| Lambert-Eaton myasthenic syndrome | Proximal weakness, areflexia, autonomic dysfunction | Anti-VGCC — SCLC |
| Myasthenia gravis | Fatigable ocular, bulbar and limb weakness | Thymoma |
| Autonomic neuropathy | Dysautonomia | SCLC, thymoma |
Anti-Yo antibodies target Yo antigens aberrantly expressed by the tumour and destroy Purkinje cells of the cerebellum. Gynaecological and breast cancers are the tumours most often associated with paraneoplastic neurological syndromes, and Yo cerebellar degeneration is the foremost of them — so the tumour search in an anti-Yo-positive woman focuses on the ovary and breast.
Lambert-Eaton myasthenic syndrome (LEMS) is caused by antibodies against presynaptic voltage-gated calcium channels, which reduce acetylcholine release. About 60% of patients have an underlying tumour, mainly SCLC, and about 3% of SCLC patients develop LEMS. Anti-VGCC antibodies are positive in about 85%.
| Feature | Lambert-Eaton | Myasthenia gravis |
|---|---|---|
| Lesion | Presynaptic — anti-VGCC, less ACh released | Postsynaptic — anti-AChR |
| Weakness | Proximal lower limbs first, spreading caudal to cranial | Commonly ocular — ptosis and diplopia |
| Repeated effort | Improves (post-exercise facilitation) | Worsens (fatigability) |
| Reflexes | Reduced or absent, improve after exercise | Normal |
| Autonomic features | Present (constipation, abnormal pupillary responses) | Absent |
| Repetitive nerve stimulation | Decrement at low rate, increment at high rate | Decrement |
| Sex | 60–75% male | Female predilection |
| Associated tumour | Small cell lung cancer | Thymoma |
Which skin signs point to an internal malignancy?
Acanthosis nigricans is velvety, thickened, hyperpigmented skin, usually in the axillae and neck. It is most commonly linked to obesity, diabetes and insulin resistance; only rarely is it paraneoplastic. Malignant acanthosis nigricans is thought to be driven by tumour-derived transforming growth factor, and gastric adenocarcinoma is the commonest associated cancer.
The sign of Leser-Trélat is the abrupt eruption of multiple seborrhoeic keratoses, often itchy and sometimes in a 'Christmas tree' pattern on the trunk. The most common underlying cancer is gastric adenocarcinoma, followed by other gastrointestinal adenocarcinomas. Generalised pruritus or acanthosis nigricans alongside should raise suspicion further, and an abrupt crop of itchy seborrhoeic keratoses warrants tumour screening.
- Dermatomyositis: heliotrope rash of the upper eyelids, Gottron papules over the knuckles, and erythema over the face, neck, back, chest and shoulders; muscle biopsy is recommended when it is suspected to be tumour-related.
- Trousseau syndrome: recurrent migratory thrombophlebitis, mainly with pancreatic and bronchogenic carcinoma.
- Hypertrophic osteoarthropathy: digital clubbing, joint swelling and pain; it can resolve after treatment of the primary cancer.
How are paraneoplastic syndromes investigated and treated?
- Basic tests: complete blood count, metabolic panel (sodium, calcium, glucose), urinalysis.
- Hormone levels: PTHrP, ACTH, ADH as indicated; 1,25-dihydroxy vitamin D when lymphoma or granulomatous disease is suspected.
- Paraneoplastic antibody panels in serum and CSF, CSF analysis and protein electrophoresis for neurological syndromes.
- Tumour search: tumour markers and imaging directed by the antibody — ovary and breast for anti-Yo, chest for anti-Hu or LEMS; repeat over time if negative.
- Biopsy: skin or muscle (for suspected tumour-related dermatomyositis).
Treatment is treatment of the underlying cancer, plus control of the syndrome itself — for example intravenous normal saline, calcitonin and bisphosphonates for hypercalcaemia, with glucocorticoids when lymphoma or granulomatous disease is producing calcitriol. Some syndromes, such as hypertrophic osteoarthropathy, resolve once the tumour is treated.