General Information

  • Small cell lung cancer (SCLC) is a malignant epithelial neuroendocrine tumor consisting of small cells with scant cytoplasm, ill-defined cellular borders, finely granular nuclear chromatin, and absent or inconspicuous nucleoli.
  • SCLC accounts for about 13%-15% of lung cancer cases; it can be further classified as pure SCLC or combined SCLC (with mixture of small and non-small cell histology)
  • It is characterized by rapid doubling time, high growth fraction, and widespread metastases early in disease; patients often present with hematogenous metastases
  • SCLC is suspected in patients with a history of cigarette smoking, coughing, hemoptysis, wheezing, dyspnea, and/or chest pain.

Risk Factors for Lung Cancer

  • Tobacco smoke
    • Almost all cases of SCLC are related to tobacco use
    • > 90% of cases occur in elderly current or past heavy smokers
    • Risk of SCLC increases with increasing duration and intensity of smoking
  • Environmental exposure to tobacco smoke increases risk of lung cancer
  • Environmental exposure to pollutants, such as asbestos, combustion-related fine particulate air pollution, and radon exposure


  • Mutations causing establishment of autocrine growth loops, activation of proto-oncogenes, or loss or inactivation of tumor-suppressors appear to be involved in pathogenesis
    • Genes commonly involved include
      • Fragile Histidine Triad (FHIT) gene – deletion observed in almost all cases
      • Retinoblastoma 1 (RB1) gene – loss observed in almost all cases
      • MAD1L1 gene
      • Tumor protein 53 (TP53) gene – more common in SCLC than non-small cell lung cancer
  • Tumor cells exhibit signs of neuroendocrine and neural differentiation, and tumor growth mediated by multiple neuropeptides and polypeptides

Clinical Presentation

  • Perform complete history (especially history of cigarette smoking) and physical examination
  • Typically with rapid onset of symptoms (typically 8-12 weeks prior to presentation)
  • Most present with extrathoracic (hematogenous) metastases; about 33% of patients present with localized disease confined to chest
  • Signs and symptoms related to local primary tumor include:
    • Dyspnea
    • Persistent cough
    • Wheezing
    • Hemoptysis, particularly if central/cavitary lesion present
    • Fever (due to pneumonia)
    • Chest pain
    • Clubbing of digits
  • Signs and symptoms related to invasive primary tumor/regional lymph node metastases include:
    • Hoarseness
    • Hemidiaphragm elevation, due to phrenic nerve compression
    • Dysphagia
    • Chest pain (often dull and nonlocalized
    • Superior vena cava (SVC) syndrome
    • Pericardial effusion/tamponade
    • cervical/supraclavicular lymphadenopathy
    • Pancoast syndrome
    • Horner syndrome
  • Signs and symptoms related to extrathoracic (hematogenous) metastases
    • Anorexia/cachexia, fatigue
    • Brain metastases: headache, focal weakness/numbness, confusion, Slurred speech, gait instability, and lack of coordination
    • Leptomeningeal carcinomatosis: headache, confusion, cranial nerve palsy, diplopia, slurred speech, radicular back pain, spinal cord compression
    • Adrenal metastases: mid-back/flank pain
    • Liver metastases: right upper quadrant pain, jaundice, and Hepatomegaly
    • Bone metastases

Making the Diagnosis

  • Suspect SCLC in patients with
    • Abnormal findings on chest x-ray
    • History of cigarette smoking
    • Signs and symptoms suggestive of lung malignancy, including coughing, hemoptysis, wheezing, fever, dyspnea, and/or chest pain
  • Initial evaluation to establish diagnosis includes:
    • Blood tests
    • Chest x-ray
    • IV contrast-enhanced computed tomography (CT) of chest, abdomen, and pelvis or of chest extending through liver and adrenal glands
  • Confirm diagnosis in patients with radiographic/clinical evidence of SCLC with the least invasive biopsy/pathology method possible, options include:
    • Sputum cytology
    • Thoracentesis
    • Bronchoscopy including transbronchial needle aspiration (TBNA)
    • Fine needle aspiration (FNA)
    • Transthoracic needle aspiration (TTNA)
  • Obtain studies for staging, including:
    • Brain MRI or IV contrast-enhanced brain CT to detect metastases
    • Bone scan
    • Initial MRI for suspected single small liver or bone metastatic lesion to avoid delay of treatment due to awaiting pathological confirmation
    • PET/CT if suspect limited stage or need clarification of stage
  • Additional workup for suspected limited stage disease may include:
    • Pulmonary function tests
    • Bone MRI or x-ray if PET/CT is inconclusive, followed by bone biopsy if MRI or bone scan is inconclusive
    • Head MRI or CT in addition to PET, or abdominal CT plus bone scan in patients with clinical stage I disease considering definitive surgery
    • Thoracentesis with cytologic analysis if pleural effusion is present
    • Bone marrow aspiration and biopsy in select patients with presentation suggestive of bone marrow involvement
  • For never smokers with extensive stage disease, consider molecular profiling to clarify diagnosis and evaluate possible targeted therapies

Differential Diagnosis

Other Cancers

  • Non-small cell lung cancer
    • Mesothelioma
    • Other lung neuroendocrine tumors
    • Primary pulmonary lymphoma
    • Malignant teratoma
    • Pulmonary blastoma – rare malignant tumor

Non-cancer Differential Diagnosis

  • Benign neoplasms (such as hamartoma, chondroma, hemangioma)
  • Infections
    • Healed/nonspecific granulomas
    • Granulomatous infections (such as tuberculosis, histoplasmosis, pulmonary aspergilloma, etc.)
    • Bacterial infection (nocardiosis, actinomycosis, pneumonia)
    • Septic embolus
    • Abscess
  • Other causes
    • Amyloid
    • Pulmonary infarction  
    • Lipoid pneumonia
    • Sarcoidosis
    • Subpleural lymph node
    • Rheumatoid arthritis
    • Granulomatosis with polyangiitis
    • Focal hemorrhage
    • Rib fracture
    • Pleural thickening/mass/fluid

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Management of Limited Stage Disease

  • If limited stage disease and
    • Negative pathologic mediastinal staging, perform lobectomy and mediastinal lymph node dissection or sampling (follow with adjuvant treatment based on findings)
      • If lymph nodes negative, offer 4 cycles of adjuvant systemic therapy
      • If lymph nodes positive, offer sequential/concurrent systemic therapy with or without mediastinal radiation
    • Positive pathologic mediastinal imaging in excess of t1-t2, n0 with:
      • Performance status (ps) 0-2, offer concurrent systemic therapy plus thoracic radiation
      • Ps 3-4 due to sclc, offer systemic therapy with or without either concurrent or sequential radiation
      • Ps 3-4 not due to sclc, offer individualized treatment plan, including use of supportive care
    • Medically inoperable disease/decision not to pursue surgical resection, consider either stereotactic ablative radiation therapy (sabr) followed by adjuvant systemic therapy or concurrent systemic therapy plus radiation
    • A complete or partial response to initial therapy, offer adjuvant prophylactic cranial irradiation

Management of Extensive Stage Disease

  • For patients with extensive stage disease:
    • If no localized symptomatic sites/brain metastases, offer supportive care and base additional treatment on performance status (PS):
      • PS 0-2 or 3-4 due to SCLC, offer systemic therapy
      • PS 3-4 not due to SCLC, offer an individualized treatment plan
    • If localized symptomatic sites with superior vena cava syndrome, lobar obstruction, or bone metastases, treatment options include:
      • Systemic therapy with or without radiation to symptomatic sites
      • Orthopedic stabilization and palliative external beam radiation (if high risk of fracture)
    • If spinal cord compression, consider radiation to symptomatic sites before systemic therapy (unless immediate systemic therapy is indicated)
    • If brain metastases, consider:
      • If patient asymptomatic, systemic therapy before whole brain radiation  
      • If patient symptomatic, whole brain radiation before systemic therapy (unless immediate systemic therapy is indicated)  
    • For patients with a complete or partial response to initial therapy, options include adjuvant prophylactic cranial irradiation or MRI surveillance of brain.
    • For those with residual thoracic disease and low-bulk metastatic disease, may also offer sequential thoracic radiation after systemic therapy


Management of Relapsed or Progressive Disease

  • Offer palliative management to all patients regardless of performance status (PS), including localized radiation to symptomatic sites
  • For patients with PS 0-2, offer systemic therapy with response assessment by chest/abdomen/pelvic CT with contrast after every 2-3 cycles
    • If response, continue therapy until disease progression/unacceptable toxicity
    • If no response or unacceptable toxicity and PS remains 0-2, options include systemic therapy and palliative symptom management

Paraneoplastic Syndromes

  • Paraneoplastic syndromes are common in SCLC; may occur months to years before malignancy is detected
  • Variety of paraneoplastic syndromes associated with lung cancer and affect many systems, including:
    •  Endocrine (such as SIADH, Cushing syndrome, hypercalcemia, carcinoid syndrome)
    • Neurologic (subacute cerebellar degeneration, encephalomyelitis, and sensory neuropathy)
    • Skeletal (hypertrophic osteoarthropathy and clubbing)
    • Renal (glomerulonephritis, nephrotic syndrome, metabolic syndrome)
    • Collagen-vascular (dermatomyositis, systemic lupus erythematosus, vasculitis, polymyositis)
    • Cutaneous (erythema multiforme, red man syndrome, acanthosis nigricans, Sweet syndrome, pruritus and urticaria)
    • Hematologic (anemia, leukemoid reaction, Trousseau syndrome, leukocytosis and eosinophilia, thrombocytopenic purpura, disseminated intravascular coagulation and thromboembolism)


  • Median survival without treatment reported to be 2-4 months
  • Factors associated with improved prognosis include:
    • Improved performance status (karnofsky performance status > 80 or ecog 0-1)
    • Female sex
    • Younger age (age < 70 years, < 65 years, and < 60 years each independently validated)
  • Brain metastases develop in up to 50% of patients with extensive stage disease


Smoking Cessation

  • American Cancer Society (ACS) recommends avoiding tobacco use, environmental tobacco smoke and avoiding radon exposure to reduce risk
  • All clinicians should provide smoking cessation interventions
    • 5-A strategy for advising patients recommended by United States Preventive Services Task Force (USPSTF)
      • Ask about tobacco use
      • Advise to quit through clear personalized messages
      • Assess willingness to quit
      • Assist to quit
      • Arrange follow-up and support
  • Combination of counseling and medication is more effective than either alone and both should be offered
  • First-line medication options include nicotine replacement therapy, varenicline, or bupropion
  • Other smoking cessation techniques may be useful include cognitive behavioral therapy, acupuncture, mind-body interventions, and hypnotherapy


  • Goal is to benefit individuals by increasing life expectancy and quality of life, but with low false-positive results to prevent additional, unnecessary testing
  • Low-dose computed tomography (ldct) screening detects lung cancer in about 1%-2% of patients who smoke or have other risk factors
  • Screening of lung cancer using ldct recommended or suggested in patients with
    • Age 55-74 years, ≥ 30 pack-year history of smoking, and smoking cessation < 15 years
    • Age ≥ 50 years, ≥ 20 pack-year history of smoking, and presence of additional risk factors that increase risk of lung cancer to ≥ 1.3%
  • Routine lung cancer screening with ldct not recommended or suggested in patients who are asymptomatic and do not meet above criteria
  • Ldct screening has high sensitivity and moderate specificity for lung cancer, but may be associated with high rate of false-positives, leading to unnecessary, invasive follow-up procedures


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  3. Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 Suppl):e142S-165S. doi:10.1378/chest.12-2353
  4. Loo BW, Akerley W, Bassetti M, et al. Small cell lung cancer. Version 2.2020. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines). Access to PDF.

This article originally appeared on Clinical Advisor