What is the management approach for a 67-year-old patient with adenocarcinoma of the lung, TTF-1 (Thyroid Transcription Factor 1) positive, and P63, synaptophysin, and chromogranin A negative?

Management Approach for Lung Adenocarcinoma with TTF-1 Positive, P63, Synaptophysin, and Chromogranin A Negative Status

The immunohistochemistry profile of TTF-1 positive, P63 negative, synaptophysin and chromogranin A negative strongly confirms primary lung adenocarcinoma and warrants molecular testing for EGFR, ALK, and other targetable mutations to guide personalized therapy with tyrosine kinase inhibitors.

Interpretation of Immunohistochemical Markers

TTF-1 (Thyroid Transcription Factor-1)

• Positive TTF-1: Strongly indicates primary pulmonary adenocarcinoma origin
  • TTF-1 is expressed in 70-100% of nonmucinous lung adenocarcinomas 1
  • TTF-1 is a homeodomain-containing nuclear transcription protein expressed in epithelial cells of embryonal and mature lung and thyroid 1
  • Metastatic adenocarcinomas to the lung are typically TTF-1 negative (except thyroid malignancies) 1

P63

• Negative P63: Supports adenocarcinoma diagnosis
  • P63 is typically positive in squamous cell carcinomas (87.5%) and negative in adenocarcinomas 2
  • The combination of TTF-1 positive/P63 negative is highly specific for adenocarcinoma 1, 3

Neuroendocrine Markers

• Negative Synaptophysin and Chromogranin A: Rules out neuroendocrine differentiation
  • These markers are used to identify neuroendocrine tumors 1
  • Their absence confirms the tumor lacks neuroendocrine features 4
  • CD56, chromogranin, and synaptophysin are standard markers for neuroendocrine differentiation 1

Diagnostic Confirmation

The immunohistochemical profile (TTF-1+/P63-/synaptophysin-/chromogranin A-) definitively confirms primary lung adenocarcinoma. This is consistent with findings from multiple studies showing that TTF-1 positivity is seen in most primary pulmonary adenocarcinomas, while P63 positivity is characteristic of squamous cell carcinomas 2, 5.

Management Algorithm

1. Complete Staging Workup

• CT chest/abdomen/pelvis with contrast
• PET-CT scan
• Brain MRI (recommended for all adenocarcinomas)
• Mediastinal staging if indicated (EBUS, mediastinoscopy)
• Determine TNM stage using AJCC 8th edition criteria 1

2. Molecular Testing (Critical)

• Preserve tissue for molecular studies - judicious use of IHC is recommended to save tissue for molecular testing 1
• Essential molecular tests:
  • EGFR mutation testing (exon 19 deletion, exon 21 L858R mutation) 1
  • ALK gene rearrangement 1
  • ROS1 rearrangement
  • BRAF V600E mutation
  • PD-L1 expression
  • KRAS mutation (may indicate resistance to EGFR TKIs) 1

3. Treatment Based on Stage and Molecular Profile

Early Stage (I-II)

• Surgical resection (lobectomy preferred) with mediastinal lymph node evaluation
• Consider adjuvant chemotherapy for stage IB (>4 cm) and stage II

Locally Advanced (Stage III)

• Multidisciplinary approach with combination of:
  • Surgery
  • Chemotherapy
  • Radiation therapy

Advanced/Metastatic (Stage IV)

• For patients with targetable mutations:

  • EGFR mutation: EGFR tyrosine kinase inhibitors (erlotinib, osimertinib) 6
    • EGFR mutations are associated with response to TKIs, especially exon 19 deletion and exon 21 L858R mutation 1
  • ALK rearrangement: ALK inhibitors (alectinib, brigatinib)
  • ROS1 rearrangement: ROS1 inhibitors (crizotinib, entrectinib)
  • BRAF V600E: BRAF/MEK inhibitor combination

• For patients without targetable mutations:

  • Immunotherapy (if PD-L1 ≥50%)
  • Chemotherapy + immunotherapy (if PD-L1 <50%)
  • Platinum-based doublet chemotherapy

Important Considerations

1. Tissue preservation: Judicious use of IHC is critical to preserve tissue for molecular testing, particularly in patients with advanced disease 1

2. Prognostic factors: TTF-1 positivity may be associated with better prognosis in some studies, though results are mixed 2

3. Molecular testing priority: EGFR mutation testing is particularly important as there is significant association between EGFR mutations and response to TKIs 1, 6

4. Common pitfalls to avoid:

   • Inadequate tissue sampling leading to insufficient material for molecular testing
   • Failure to test for all relevant molecular markers
   • Initiating treatment before molecular testing results are available in advanced disease
   • Not considering clinical factors (smoking status, gender, ethnicity) that correlate with mutation prevalence

5. Napsin A testing: Consider adding Napsin A to the immunopanel as it appears to be expressed in >80% of lung adenocarcinomas and may be a useful adjunct to TTF-1 1, 7

The TTF-1 positive, P63 negative, synaptophysin and chromogranin A negative immunoprofile provides strong evidence for primary lung adenocarcinoma, and molecular testing should be prioritized to identify potential targets for personalized therapy that can significantly improve outcomes.