Paraneoplastic Syndromes

Intro & Mechanisms - Cancer's Covert Ops

• Systemic disorders triggered by cancer, not due to direct tumor invasion, metastasis, or side effects of therapy.
• Caused by tumor-secreted hormones, peptides, cytokines, or aberrant immune responses.
• Common Mechanisms:
  • Ectopic hormone/peptide production (e.g., ACTH, ADH).
  • Immune cross-reactivity: Antibodies or T-cells against tumor also target normal tissues.
  • Cytokine release (e.g., TNF-α, IL-6) leading to systemic inflammation/cachexia.

⭐ Paraneoplastic syndromes can be the first manifestation of an underlying malignancy, often preceding cancer diagnosis by months or years.

Endocrine Syndromes - Hormone Hijack

• SIADH (Hyponatremia): Ectopic ADH secretion.
  • Associated with: Small Cell Lung Cancer (SCLC), CNS disorders, drugs.
  • Clinical: ↓Na+, ↓serum osmolality, ↑urine osmolality.
• Cushing's Syndrome: Ectopic ACTH secretion.
  • Associated with: SCLC, pancreatic cancer, bronchial carcinoids.
  • Clinical: HTN, hyperglycemia, hypokalemia, muscle weakness, central obesity.
• Hypercalcemia: PTHrP (PTH-related peptide) most common; also ectopic PTH, calcitriol.
  • Associated with: Squamous cell (lung, head/neck), renal, breast, ovarian cancer.
  • Clinical: "Stones, bones, groans, thrones, psychiatric overtones".
• Hypoglycemia: Ectopic Insulin or IGF-2.
  • Associated with: Fibrosarcoma, mesenchymal tumors, hepatocellular carcinoma.
• Carcinoid Syndrome: Serotonin, bradykinin.
  • Associated with: Metastatic carcinoid tumors (bronchial, GI).
  • Clinical: Flushing, diarrhea, bronchospasm, right-sided heart valve lesions.
• Polycythemia: Ectopic erythropoietin.
  • Associated with: Renal cell carcinoma, hepatocellular carcinoma, hemangioblastoma.

⭐ Small Cell Lung Cancer (SCLC) is notorious for causing SIADH (hyponatremia) and ectopic ACTH production (Cushing's syndrome).

Word count: 98

Neurological Syndromes - Nervous System Mayhem

• Central Nervous System (CNS):
  • Limbic Encephalitis: Confusion, seizures, memory loss. Assoc: SCLC (Anti-Hu), testicular (Anti-Ma2).
  • Paraneoplastic Cerebellar Degeneration: Ataxia, dysarthria. Assoc: Ovarian/Breast (Anti-Yo), Hodgkin (Anti-Tr), SCLC (Anti-Hu).
  • Opsoclonus-Myoclonus Syndrome: "Dancing eyes, dancing feet". Assoc: Neuroblastoma (children), SCLC/Breast (adults, Anti-Ri).
  • Brainstem Encephalitis: Cranial neuropathies, gaze palsies.
• Peripheral Nervous System & Neuromuscular Junction (NMJ):
  • Lambert-Eaton Myasthenic Syndrome (LEMS):

    ⭐ Associated with SCLC, classically presents with proximal muscle weakness that improves with repeated muscle contraction. (📌 LEMS: Lungs, Exercise-improves, Myasthenic Syndrome)

    • Antibodies: Voltage-gated Ca²⁺ channels (VGCC).
  • Myasthenia Gravis: Fluctuating weakness, worse with exertion. Assoc: Thymoma. Antibodies: AChR.
  • Peripheral Neuropathy: Sensory, motor, or mixed. Often painful.
  • Stiff-Person Syndrome: Muscle rigidity, spasms. Assoc: Breast Ca, SCLC (Anti-amphiphysin), GAD Ab.

Other Key Syndromes - Systemic Shenanigans

• Hematological:
  • Trousseau's syndrome (migratory thrombophlebitis): Pancreas, Lung
  • Granulocytosis (↑WBCs): Lung, GI (G-CSF mediated)
  • Eosinophilia: Hodgkin lymphoma
  • Pure red cell aplasia: Thymoma
  • NBTE (marantic endocarditis): AdenoCa (mucinous)
• Dermatological:
  • Leser-Trélat sign (abrupt seborrheic keratoses): GI adenoCa
  • Dermatomyositis/Polymyositis: Ovary, Lung, GI, Lymphoma
  • Sweet's syndrome (acute febrile neutrophilic dermatosis): AML
  • Necrolytic migratory erythema: Glucagonoma

  ⭐ Acanthosis nigricans in a non-obese adult, especially with rapid onset and extensive involvement, strongly suggests an underlying GI adenocarcinoma.

• Rheumatological:
  • Hypertrophic osteoarthropathy (HOA; clubbing, periostitis): Lung (NSCLC)
  • Palmar fasciitis & polyarthritis ("puffy hand syndrome"): Ovary, Breast

Diagnosis & Management - Cracking the Case

• Diagnostic Approach
  • High suspicion; rule out mimics (metastasis, metabolic, infection).
  • Tests: Paraneoplastic antibody panels (anti-Hu, Yo, Ri), imaging (CT, PET-CT) for occult tumor.
• Management Strategy
  • Primary: Treat underlying cancer (curative intent if possible).
  • Adjunctive: Symptomatic relief; immunosuppression (steroids, IVIG, PLEX) for autoimmune types.

⭐ The definitive treatment for most paraneoplastic syndromes is successful treatment of the underlying cancer.

High‑Yield Points - ⚡ Biggest Takeaways

• SCLC: Key for SIADH (hyponatremia), ectopic ACTH (Cushing's), LEMS.
• Squamous cell lung ca: Produces PTHrP, leading to hypercalcemia.
• LEMS: Anti-presynaptic Ca²⁺ channels; weakness improves with activity.
• MG: Anti-postsynaptic AChR; linked to thymoma; weakness worsens with activity.
• Acanthosis nigricans: Velvety skin plaques; strong association with gastric/GI adenocarcinoma.
• Dermatomyositis/Polymyositis: High risk of underlying occult malignancy (ovarian, lung, GI).
• Hypertrophic Osteoarthropathy (HOA): Digital clubbing, periostitis; frequently linked to lung cancer.