Paraneoplastic Syndromes

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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).

Endocrine Paraneoplastic Syndromes and Associated Tumors 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.

Paraneoplastic CNS syndromes overview

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 Acanthosis nigricans in axilla

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.

Practice Questions: Paraneoplastic Syndromes

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