326.1 🎓 醫孞生版

326.1.0.1 📌 䞀頁重點

326.1.0.1.1 Small Cell Lung Cancer (SCLC)
326.1.0.1.1.1 Epidemiology
  • 15% of lung cancers
  • Almost exclusively smokers (> 95%)
  • Aggressive, rapid growth
  • Often metastatic at diagnosis (60-70%)
  • Improving outcomes with immunotherapy
  • 5-year survival: limited 25-30%, extensive 5-10%
326.1.0.1.1.2 Pathology
  • Neuroendocrine origin
  • Small, “oat” cells; scant cytoplasm; salt-and-pepper chromatin
  • Necrosis, high mitotic rate
  • Markers: chromogranin, synaptophysin, CD56, INSM1
  • TP53 + RB1 mutations universal (key oncogenic drivers)
  • ASCL1 + NEUROD1 subtypes (emerging)
326.1.0.1.1.3 Staging — VALG vs TNM

Veterans Affairs Lung Cancer Study Group (VALG): - Limited-stage (LS-SCLC): - Confined to one hemithorax - Encompassed by single radiation port - Ipsilateral mediastinal + supraclavicular LN - Extensive-stage (ES-SCLC): - Beyond above - Contralateral lung - Distant mets

TNM 8th Edition also applies; modern staging combines

326.1.0.1.1.4 Clinical Features

Local Symptoms: - Cough, dyspnea, chest pain - Hemoptysis - Hoarseness (RLN) - Dysphagia - SVC syndrome (mediastinal extension)

Metastatic Disease: - Liver - Bone - Brain - Adrenal

Paraneoplastic Syndromes (Most Common in SCLC):

SIADH: - ~ 10% of SCLC - Hyponatremia - ADH ectopic secretion - Treatment: fluid restriction, tolvaptan, demeclocycline, hypertonic saline (acute severe)

Cushing Syndrome (Ectopic ACTH): - ~ 5% of SCLC - Severe hyperglycemia, hypokalemic alkalosis, hypertension, edema - Onset rapid (vs pituitary Cushing) - High ACTH levels - Treatment: ketoconazole, mitotane, etomidate, mifepristone, metyrapone; surgical for localized

Lambert-Eaton Myasthenic Syndrome (LEMS): - ~ 3% of SCLC - Anti-VGCC antibodies (voltage-gated calcium channels) - Proximal weakness, autonomic dysfunction, hyporeflexia - Improves with repeated effort (vs MG which worsens) - EMG: decremented amplitude with low-frequency stim; FACILITATION at high frequency - Treatment: 3,4-diaminopyridine, IVIG, plasmapheresis; treat underlying cancer

Limbic Encephalitis: - Anti-Hu, anti-CV2, anti-Ma2 antibodies - Memory + confusion + seizures + behavioral changes - Treatment: IS + treat cancer; often refractory

Other Paraneoplastic: - Encephalomyelitis (anti-Hu) - Cerebellar degeneration - Sensory neuropathy - Opsoclonus-myoclonus

326.1.0.1.1.5 Diagnosis
  • Tissue biopsy + IHC (neuroendocrine markers)
  • TP53 + RB1 typical
  • Imaging: CT + PET-CT + brain MRI
  • Bone marrow biopsy if cytopenia
  • LFTs, electrolytes (paraneoplastic)
326.1.0.1.1.6 Treatment

Limited-Stage SCLC (LS-SCLC): - Concurrent chemoradiation (cisplatin + etoposide + radiation 45 Gy BID or 60-70 Gy daily) - PCI (prophylactic cranial irradiation) for those with complete response (25 Gy in 10 fractions) - 30-40% 5-year survival in select

Extensive-Stage SCLC (ES-SCLC): - Chemotherapy + Immunotherapy: - Carboplatin + Etoposide + Atezolizumab (IMpower133, 2018) - Cisplatin or Carboplatin + Etoposide + Durvalumab (CASPIAN, 2019) - Both ↑ median OS modestly (~ 12-13 months vs ~ 10 months) - Maintenance IO until progression - Brain MRI surveillance (PCI controversial in ES-SCLC)

Second-Line + Beyond: - Topotecan (oral or IV) - Lurbinectedin (Zepzelca) — 2020 FDA, after platinum - TARLATAMAB (Imdelltra) — 2024 FDA, DLL3-targeted BiTE (bispecific T-cell engager) - DeLLphi-301 trial (2024): 40% response rate - Game-changing in pretreated SCLC - Re-challenge with platinum if long platinum-free interval - Investigational: PARP inhibitors (olaparib, talazoparib)

Brain Mets: - Common (50%+) - WBRT, SRS - Specific TKIs limited

Spinal Cord Compression: - Common - Emergent radiation + steroids - Surgical decompression if appropriate

326.1.0.1.2 Neuroendocrine Tumors of Lung — Spectrum

326.1.1 Typical Carcinoid Tumor

  • Well-differentiated
  • Slow-growing
  • < 2 mitoses per 10 HPF, no necrosis
  • Surgical resection curative (90%+ 5-year)
  • Octreotide if symptomatic
  • 5-HT secretion → carcinoid syndrome (right-sided heart valves)

326.1.2 Atypical Carcinoid Tumor

  • Moderately differentiated
  • 2-10 mitoses per 10 HPF, ± necrosis
  • More aggressive than typical
  • Surgical + adjuvant

326.1.3 Large Cell Neuroendocrine Carcinoma (LCNEC)

  • Poorly differentiated

  • 10 mitoses per 10 HPF

  • Aggressive
  • Treatment: similar to SCLC (chemo) or NSCLC (depends)

326.1.4 Small Cell Lung Cancer (SCLC)

  • Most poorly differentiated

  • 11 mitoses per 10 HPF

  • Most aggressive
  • Treatment above
326.1.4.0.1 Paraneoplastic Syndromes — Broader Discussion

326.1.5 General Mechanisms

  • Ectopic hormone secretion (PTHrP, ACTH, ADH)
  • Antibody-mediated (autoimmune, cross-reactivity)
  • Cytokine-mediated (paraneoplastic inflammation)
  • Coagulation activation (hypercoagulability)

326.1.6 By Cancer Type

SCLC: - SIADH (hyponatremia) - Cushing (ectopic ACTH) - LEMS (anti-VGCC) - Limbic encephalitis (anti-Hu) - Cerebellar degeneration

Squamous Cell Carcinoma: - PTHrP → hypercalcemia (classic)

Adenocarcinoma: - Hypertrophic pulmonary osteoarthropathy (HPOA) + clubbing - Trousseau syndrome

Non-Specific: - Anemia, cachexia - DIC - Anemia of chronic disease - Erythrocytosis (rare; renal cell, hepatocellular more common)

326.1.7 Treatment of Paraneoplastic Syndromes

  • Often improves with treatment of underlying cancer
  • Specific symptomatic treatment also needed:
    • SIADH: fluid restriction, tolvaptan
    • Hypercalcemia: IV fluids, bisphosphonates, calcitonin, denosumab
    • Cushing: ketoconazole, metyrapone, etomidate, mifepristone
    • LEMS: 3,4-diaminopyridine, IVIG, plasmapheresis
    • Encephalitis: IVIG, plasmapheresis, rituximab

326.1.7.1 🩺 床邊速查

  • SCLC: smokers >95%, aggressive, central, neuroendocrine, TP53+RB1 universal
  • Staging: LS-SCLC vs ES-SCLC; TNM 8th also
  • LS-SCLC: cisplatin + etoposide + chemoradiation + PCI
  • ES-SCLC: carboplatin + etoposide + atezolizumab (IMpower133) or durvalumab (CASPIAN)
  • Refractory SCLC: tarlatamab (DLL3 BiTE, 2024 FDA, DeLLphi-301) — 40% response
  • Paraneoplastic SCLC: SIADH, Cushing (ACTH), LEMS (anti-VGCC), limbic encephalitis
  • Carcinoid: typical (slow) vs atypical (aggressive); surgery curative
  • LCNEC: between SCLC + NSCLC, treat as SCLC mostly