Cytologically Yours: Unknowns: 201310: Case 1

Clinical History

55 year old male with a right upper lobe lung mass and mediastinal adenopathy. The patient is a smoker.

Cytology

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Resident Questions

• Diagnosis?

Adenocarcinoma.

• What genetic mutations, if any, are associated with this diagnosis?

• EGFR testing is performed on these tumors to select patients for tyrosine kinase inhibitor (TKI)therapy (Gefitinib).
• Patients with EML4-ALK fusion, respond to ALK inhibitor (ALKI) (Crizotinib)
  • Deletion and inversion on Chromosome 2p
• Patients with KRAS or BRAF mutation do not respond to TKI, ALKI
• KRAS mutations tend to be an adverse prognostic sign
  • Seen in mucinous type tumors, smokers and those of non-Asian ancestry
  • Most common mutations are in codons 12 and 13 of exon 2
• EGFR
  • Point mutation or substitution mutation in the EGFR tyrosine kinase domain
    • Sensitive to EGFR tyrosine kinase inhibitors
      • Exons 19 deletion
      • Exon 21 L858R
      • Exon 18 G719
    • Resistance to EGFR tyrosine kinase inhibitors
      • Exon 20 (insertion V769L, S768I)
      • Exon 19 (D761Y)

• Why is it important to distinguish between adenocarcinoma and squamous cell carcinoma?

• Treatment
  • EGFR mutations are found in adenocarcinoma and in some adenosquamous carcinomas
  • Bevacizumab is a monoclonal antibody that blocks vascular endothelial growth factor A (VEGF-A), which stimulates angiogenesis in cancer
  • Association between fatal hemoptysis in patients with squamous cell carcinoma of the lung treated with Bevacizumab
    • Therefore, Bevacizumab is contraindicated for tumors with squamous cell histology

Additional Teaching Points

Immunohistochemistry

• TTF-1 (nuclear stain)
  • Thyroid Transcription factor1 regulates transcription of genes specific to the thyroid, lung, and diencephalon
  • If metastatic thyroid cancer to the lung is ruled out by morphology or +thyroglobulin; then a +TTF1 supports adenocarcinoma originating from the lung
• P63 (nuclear stain) and 34BE12 (cytoplasmic stain)
  • Used for squamous differentiation
• TTF1 is more sensitive than p63
  • If a tumor stains for both it is more likely to be adenocarcinoma
• Napsin A(cytoplasmic stain)
  • Granular staining pattern
  • Marker for adenocarcinoma