Molecular Pathology of Lung Cancer

PATHCHAT Edition No. 65
January 2020
Please contact your local Ampath pathologist for more information.

Author: Dr. Henno Olivier (Histopathologist)

Introduction

✅ Lung Cancer Overview:

• Lung cancer is the most common malignancy worldwide after non-melanocytic skin cancer.
• Responsible for 1.59 million deaths annually.
• Smoking contributes to 70% of lung cancer cases.

✅ Types of Lung Cancer:

• Non-Small Cell Lung Cancer (NSCLC) (80–90% of cases).
  • Subtypes:
    • Adenocarcinoma (increasing incidence).
    • Squamous Cell Carcinoma (SCC) (decreasing incidence).
• Small Cell Lung Cancer (SCLC) (declining globally).

✅ Epidemiological Trends:

• Previously more common in men, but incidence in women is rising.
• 90% of cases occur in individuals >45 years, but rare cases occur in adolescents and children.
• 10–15% of lung cancers occur in never-smokers (75% of these are adenocarcinomas, predominantly in women).

📌 Most lung cancers present at an advanced stage, leading to poor survival rates (17% five-year survival).

Diagnosis and Classification

✅ Minimally Invasive Diagnostic Techniques:

• Bronchoscopy (for centrally located lesions):
  • Bronchial washing.
  • Brushing.
  • Bronchial/transbronchial biopsy.
• Endobronchial Ultrasound (EBUS)-Guided Biopsy:
  • 75–85% diagnostic yield for centrally located lesions.
• Transthoracic Percutaneous Fine Needle Aspiration (FNA)/Core Biopsy:
  • Up to 88% diagnostic accuracy.
  • Risk of pneumothorax in up to 50% of cases.
• Thoracentesis (if pleural effusion present).

✅ Histological Diagnosis of NSCLC:

• Cornerstone of treatment decisions.
• Based on WHO classification criteria.
• Immunohistochemistry (IHC) improves accuracy:
  • Reduces NSCLC-NOS (not otherwise specified) diagnoses to <10%.

📌 Histology remains the gold standard for lung cancer classification, supplemented by molecular testing.

Molecular Biology of Lung Cancer

✅ Oncogene Addiction & Targeted Therapy:

• Certain driver mutations are essential for tumour survival ("oncogene addiction").
• Targeting these mutations leads to tumour cell death.

✅ Key Molecular Biomarkers in NSCLC:

• EGFR (Epidermal Growth Factor Receptor).
• ALK (Anaplastic Lymphoma Kinase).
• ROS1.
• BRAF.

📌 Molecular profiling of lung cancer guides the use of targeted therapies, improving survival outcomes.

Molecular Targets with Approved Therapies

✅ 1. EGFR Mutations (Epidermal Growth Factor Receptor):

• Transmembrane protein with tyrosine kinase activity.
• Common in younger, non-smoking, female patients.
• Most frequent mutations:
  • Exon 19 deletion.
  • Exon 21 L858R mutation.
• Targeted Therapies:
  • Erlotinib, Gefitinib (First-generation TKIs).
  • Osimertinib (for T790M resistance mutation).

✅ 2. ALK Rearrangements (Anaplastic Lymphoma Kinase):

• Fusion with EML4 gene (EML4-ALK fusion).
• Common in younger, non-smoking patients.
• Detected via Fluorescence In Situ Hybridization (FISH).
• Targeted Therapies:
  • Crizotinib, Alectinib, Ceritinib.

✅ 3. ROS1 Rearrangements:

• Tyrosine kinase receptor in insulin receptor family.
• Gene fusions activate ROS1 kinase domain.
• Targeted Therapy:
  • Crizotinib.

✅ 4. BRAF Mutations:

• Present in 3% of lung adenocarcinomas.
• Common in current or former smokers.
• Half of cases involve V600E substitution.
• Targeted Therapies:
  • Vemurafenib, Dabrafenib.

📌 Molecular testing determines eligibility for targeted therapies, improving patient survival.

Emerging Molecular Targets & Potential Therapies

✅ Newly Investigated Molecular Targets:

• ERBB2 (HER2).
• MET.
• RET.
• NTRK (Neurotrophic Receptor Tyrosine Kinase).
• FGFR (Fibroblast Growth Factor Receptor).

📌 Further research is needed before routine clinical adoption of these targets.

Liquid Biopsy & Cell-Free DNA Testing

✅ What Is Liquid Biopsy?

• Detects circulating tumour DNA (ctDNA) in the bloodstream.
• Uses PCR-based and Next-Generation Sequencing (NGS) methods.

✅ Clinical Applications:

• Determining eligibility for targeted therapy.
• Monitoring treatment response.
• Detecting resistance mutations (e.g., EGFR T790M).

📌 A study showed an 89.1% concordance rate between tissue and cfDNA analysis for EGFR mutations.

Cancer Immunotherapy & PD-L1 Testing

✅ Immune Evasion in Tumours:

• Tumours evade immune response by:
  • Suppressing histocompatibility antigen expression.
  • Outgrowing antigen-negative variants.
  • Upregulating immunosuppressive factors (TGF-β, PD-L1).

✅ PD-L1 & Immunotherapy:

• PD-L1 overexpression allows tumours to escape immune attack.
• Checkpoint inhibitors block PD-1/PD-L1 interactions, restoring immune response.

✅ Approved PD-L1 Inhibitor:

• Pembrolizumab (for advanced/metastatic NSCLC with PD-L1 expression).
• PD-L1 expression must be confirmed via immunohistochemistry (IHC).

📌 Checkpoint inhibitors have revolutionized lung cancer treatment, significantly improving survival rates.

Conclusion

✅ Lung cancer treatment has evolved significantly with targeted therapies and immunotherapy.
✅ Molecular testing is essential to identify actionable mutations in NSCLC.
✅ Liquid biopsy is emerging as a useful tool for monitoring disease progression.
✅ Checkpoint inhibitors targeting PD-L1 improve survival in selected patients.

📌 Molecular diagnostics now play an integral role in guiding precision medicine for lung cancer patients.