Non–Small Cell Lung Cancer

Definition

• NSCLC makes up ~85% of all lung cancers.
• It grows and spreads more slowly than small cell lung cancer (SCLC).
• Divided into three main histologic subtypes.

Major Subtypes

• Adenocarcinoma
  • Most common type (especially in non-smokers)
  • Often peripheral in the lung
  • Can be associated with EGFR, ALK, or KRAS mutations
• Squamous Cell Carcinoma
  • Strongly associated with smoking
  • Typically central (near bronchi)
  • May cavitate and cause hemoptysis
• Large Cell Carcinoma
  • Poorly differentiated
  • Can occur anywhere in the lung
  • Aggressive behavior

Common Genetic Mutations

• EGFR mutation: more common in non-smokers, women, Asians
• ALK rearrangements: associated with younger, non-smoking patients
• KRAS mutations: common in smokers; resistant to EGFR-targeted therapy
• Others: ROS1, BRAF, MET, RET, HER2

Risk Factors

• Smoking (most significant)
• Secondhand smoke exposure
• Environmental exposures (asbestos, radon, air pollution)
• Genetic predisposition (family history)

Clinical Presentation

• Often asymptomatic in early stages
• Later symptoms: Cough, Hemoptysis, Dyspnea, Chest pain, Weight loss, Hoarseness, dysphagia (from tumor compression), Paraneoplastic syndromes (e.g., hypercalcemia in squamous cell carcinoma)

Staging Approach

• TNM system (Tumor, Node, Metastasis):
  • Stage I–II: localized
  • Stage III: locally advanced
  • Stage IV: distant metastasis
• Imaging: CT chest, PET-CT, brain MRI (for stage III/IV)
• Biopsy: confirms subtype and allows molecular testing
• Mediastinal staging: EBUS, mediastinoscopy as needed

Treatment Options

Depends on stage and molecular profile:

• Early-stage (I–II):
  • Surgery (lobectomy preferred)
  • +/- adjuvant chemotherapy or radiation
• Locally advanced (Stage III):
  • Combined chemoradiotherapy
  • +/- surgery in select cases
• Advanced/metastatic (Stage IV):
  • Targeted therapy if actionable mutation present:
    • EGFR: osimertinib
    • ALK: alectinib, lorlatinib
    • ROS1: crizotinib
  • Immunotherapy: PD-1/PD-L1 inhibitors (e.g., pembrolizumab) for tumors expressing PD-L1
  • Chemotherapy: platinum-based doublets (cisplatin/carboplatin + pemetrexed or paclitaxel)