A 62-year-old woman with no smoking history presents with progressive dyspnoea and chest pain. Chest X-ray shows a 5 cm mass in the left lower lobe with pleural involvement. CT chest confirms T4N2M0 disease. Bronchoscopy shows no endobronchial lesion. Biopsy reveals a well-differentiated tumour with mucin-producing glandular structures and absence of keratinization. Immunohistochemistry is positive for TTF-1 and CK7. What is the most likely histological type and what is the significance of TTF-1 positivity?

Explanation

## Diagnosis: Adenocarcinoma with TTF-1 Positivity **Key Point:** Adenocarcinoma is characterized by mucin-producing glandular structures and is the most common lung cancer in non-smokers. TTF-1 (Thyroid Transcription Factor-1) is a lineage-specific marker of lung and thyroid origin. ## Histological Features of Adenocarcinoma | Feature | Adenocarcinoma | Squamous Cell | Large Cell | |---------|---|---|---| | **Glandular structures** | Present (hallmark) | Absent | Absent | | **Mucin production** | Present | Absent | Absent | | **Keratinization** | Absent | Present | Absent | | **Smoking association** | Weak (30%) | Very strong (90%) | Strong | | **Location** | Peripheral (distal airways) | Central (proximal airways) | Variable | | **TTF-1 positivity** | 80–90% | 10–20% | Variable | ## Immunohistochemical Profile **High-Yield:** Adenocarcinoma shows: - **TTF-1 positive** (80–90% of cases) — indicates pulmonary origin - **CK7 positive** — cytokeratin 7 (adenocarcinoma marker) - **CK20 negative** — helps exclude colorectal metastasis - **Mucin stains positive** (PAS, mucicarmine) **Mnemonic: ACE-TTF** — Adenocarcinoma, CK7+, Epithelial, TTF-1+ (lung origin) ## Clinical Significance of TTF-1 **Clinical Pearl:** TTF-1 positivity has multiple implications: 1. **Confirms pulmonary origin** — rules out metastatic adenocarcinoma from stomach, colon, or pancreas 2. **Prognostic marker** — TTF-1+ adenocarcinomas have slightly better prognosis than TTF-1– adenocarcinomas 3. **Therapeutic relevance** — helps guide molecular testing for EGFR mutations and ALK rearrangements (more common in TTF-1+ adenocarcinomas) 4. **Peripheral location** — TTF-1+ adenocarcinomas typically arise from peripheral airways (Clara cells, type II pneumocytes) ## Why Peripheral Location Matters **Warning:** Adenocarcinoma arises from distal airways and can present as a peripheral nodule without endobronchial involvement — this patient had no endobronchial lesion on bronchoscopy, which is consistent with adenocarcinoma, NOT squamous cell carcinoma (which typically shows central/endobronchial involvement). ## Staging & Prognosis Context This patient has T4N2M0 disease (stage IIIB) with pleural involvement, indicating locally advanced but potentially resectable disease. TTF-1 positivity supports molecular profiling for targeted therapy (EGFR inhibitors, ALK inhibitors).