Paraneoplastic Syndromes
A Step 1–focused lesson on paraneoplastic syndromes: the classic tumor → mediator → syndrome triads (SIADH/Cushing/LEMS with SCLC, PTHrP hypercalcemia, ectopic EPO, MG/thymoma, anti-NMDA/ovarian teratoma), the vignette buzzwords, and the next-best-step decisions for diagnosis and management.
What paraneoplastic syndromes are
Paraneoplastic syndromes are remote effects of a tumor caused by tumor-secreted substances (hormones, cytokines, procoagulants) or by immune cross-reactivity — antibodies raised against a tumor antigen that also attack normal host tissue. They are NOT due to direct mass effect, local invasion, or metastasis.
Why the boards love them:
- They can be the first clue to an occult cancer (e.g., new-onset SIADH in a smoker → hunt for small cell lung cancer).
- Severity does not correlate with tumor stage or burden.
- Hormonal syndromes usually resolve when the tumor is treated; antibody-mediated neurologic damage is often irreversible.
The exam tests classic tumor → mediator → syndrome triads plus the vignette buzzword. Learn to name the mediator and pick the next best step.
- SIADH → ectopic ADH → small cell lung cancer (SCLC); euvolemic hyponatremia, low serum osm, inappropriately high urine osm/Na⁺
- Ectopic Cushing → ectopic ACTH → SCLC (also bronchial carcinoid); hypokalemia, metabolic alkalosis, hyperglycemia, HTN, weakness; ↑ACTH not suppressed by high-dose dexamethasone
- Humoral hypercalcemia of malignancy → PTHrP → squamous cell lung, renal cell, breast, HTLV-1 adult T-cell leukemia; ↑Ca²⁺, ↓PTH, ↓phosphate
- Hypercalcemia via 1,25-(OH)₂ vitamin D → lymphoma (macrophage 1α-hydroxylase)
- Secondary polycythemia → ectopic EPO → renal cell carcinoma, hepatocellular carcinoma, hemangioblastoma, pheochromocytoma, leiomyoma
- Trousseau syndrome (migratory superficial thrombophlebitis) → procoagulants/mucin → pancreatic adenocarcinoma, lung
- Lambert-Eaton (LEMS) → anti–P/Q-type voltage-gated Ca²⁺ channel Ab → SCLC; proximal weakness that improves with repeated use, hyporeflexia, autonomic signs (dry mouth)
- Myasthenia gravis → anti-AChR Ab → thymoma; weakness worsens with use, ocular/bulbar
- Cerebellar degeneration → anti-Yo/PCA-1 (breast, ovary); anti-Hu/ANNA-1 (SCLC) → encephalomyelitis/sensory neuronopathy
- Anti-NMDA receptor encephalitis → ovarian teratoma; young woman with psychiatric change + seizures
- Acanthosis nigricans and sudden sign of Leser-Trélat (eruptive seborrheic keratoses) → gastric adenocarcinoma
- Dermatomyositis → heliotrope rash, Gottron papules → occult visceral cancer (ovary, lung, GI)
Syndrome → mediator → tumor → clue
| Syndrome | Mediator | Classic tumor | Vignette clue |
|---|---|---|---|
| SIADH | ADH | Small cell lung | Euvolemic hyponatremia |
| Ectopic Cushing | ACTH | Small cell lung | ↓K⁺; no dexamethasone suppression |
| Hypercalcemia | PTHrP | Squamous cell lung, renal | ↑Ca²⁺, ↓PTH, ↓phosphate |
| Polycythemia | EPO | Renal cell, hepatocellular | ↑Hct with normal O₂ sat |
| LEMS | Anti-Ca²⁺ channel | Small cell lung | Weakness improves with use |
| Myasthenia gravis | Anti-AChR | Thymoma | Weakness worsens with use |
| Anti-NMDA encephalitis | Anti-NMDAR | Ovarian teratoma | Young woman: psychosis + seizures |
| Trousseau | Procoagulants | Pancreatic | Migratory thrombophlebitis |
Stem: A 62-year-old man with a 40-pack-year history has a hilar mass, nausea, and confusion. Na⁺ 118, serum osm 245, urine osm 480, urine Na⁺ 60; he is clinically euvolemic with normal cortisol and TSH.
Diagnosis: SIADH from small cell lung cancer (ectopic ADH).
Next best step:
- Acutely symptomatic (seizure, coma) → hypertonic 3% saline.
- Chronic/mild → fluid restriction ± ADH-receptor antagonist (vaptan).
- Correct Na⁺ slowly (≤8 mEq/L per 24 h) to avoid osmotic demyelination syndrome.
- Definitive fix = treat the tumor (chemotherapy), which reverses the SIADH.
Stem: A 58-year-old smoker reports months of proximal leg weakness, dry mouth, and erectile dysfunction. Reflexes are absent at rest but strength and reflexes improve after sustained contraction.
Diagnosis: Lambert-Eaton myasthenic syndrome — anti–P/Q-type voltage-gated Ca²⁺ channel antibodies.
Next best step: Send anti-VGCC antibodies and — critically — get a CT chest to search for small cell lung cancer, since LEMS frequently precedes the cancer diagnosis. Symptomatic therapy = amifampridine (3,4-diaminopyridine); treating the tumor improves weakness.
Contrast: MG weakness worsens with use; repetitive nerve stimulation is decremental in MG but incremental in LEMS.
The small cell lung cancer package (memorize as one unit):
- SIADH (ectopic ADH)
- Ectopic Cushing (ectopic ACTH)
- Lambert-Eaton (anti-Ca²⁺ channel) and anti-Hu encephalomyelitis
Match the hypercalcemia mediator to the tumor:
- PTHrP → squamous cell lung, renal cell, breast (think "PTHrP = squamous")
- 1,25-vitamin D → lymphoma
- Osteolysis / bone mets → multiple myeloma, breast, bone metastases
Ectopic EPO → polycythemia (the "big-organ" tumors): renal cell, hepatocellular, hemangioblastoma, pheochromocytoma, leiomyoma.
Board approach — three moves
1) Recognize the syndrome from labs/buzzwords and name the mediator — that is usually the tested point.
2) Find the tumor. A new paraneoplastic syndrome triggers targeted, age-appropriate imaging: unexplained SIADH, Cushing, or LEMS in a smoker → CT chest for SCLC; migratory thrombophlebitis → image the pancreas; anti-NMDA encephalitis in a young woman → pelvic US/MRI for ovarian teratoma.
3) Treat. Definitive therapy is treating the underlying cancer, which reverses most hormonal syndromes; antibody-mediated neurologic syndromes may need immunotherapy and often recover only partially. Symptom bridges: SIADH → fluid restriction/hypertonic saline; hypercalcemia → IV normal saline + calcitonin + bisphosphonate; LEMS → amifampridine.
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