Title Advanced Lung Adenocarcinoma in a Non-Smoker: Unravelling Diagnostic Challenges with Immunohistochemistry and Atypical Marker Profiles Introduction Lung adenocarcinoma is the most common subtype of non-small cell lung cancer (NSCLC), increasingly diagnosed in non-smokers. In these patients, vague symptoms and misleading tumor markers often delay diagnosis. Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9), commonly associated with gastrointestinal malignancies, may be elevated in lung cancer, complicating workup. This case illustrates how immunohistochemistry (IHC) enabled diagnostic clarity in a non-smoker with metastatic disease and atypical biochemical features.

Case Presentation A 75-year-old non-smoking male presented with fatigue, anorexia, weight loss, and a chronic cough. Laboratory evaluation revealed elevated CEA (60.4 ng/mL) and CA 19-9 (763.3 U/mL). PET-CT showed a right middle lobe lung mass with mediastinal lymphadenopathy and liver metastases. Due to elevated GI tumor markers and liver involvement, a gastrointestinal primary was initially suspected. Liver lesion biopsy revealed poorly differentiated carcinoma. IHC showed strong positivity for CK7, TTF-1, NAPSIN-A, and CK19; focal positivity for CDX2; and negativity for CK20 and HepPar1 — confirming primary lung adenocarcinoma. The patient received Pemetrexed and Carboplatin. Molecular testing was not completed before therapy. He deteriorated and was transitioned to palliative care.

Discussion This case highlights how tumor marker elevation and metastatic pattern can obscure the diagnosis of lung adenocarcinoma, particularly in non-smokers. CA 19-9 and focal CDX2 positivity initially suggested gastrointestinal origin. However, robust expression of TTF-1 and NAPSIN-A confirmed pulmonary origin, emphasizing the diagnostic utility of IHC in metastatic disease of uncertain origin. Focal CDX2 staining has been documented in poorly differentiated lung adenocarcinomas, and its presence should not outweigh the significance of lung-specific markers. The reliance on tumor markers alone risks misclassification, especially when imaging patterns are nonspecific. Moreover, non-smokers frequently harbor actionable driver mutations like EGFR or ALK. Unfortunately, molecular profiling was delayed, precluding timely personalized therapy. This reflects a common clinical gap where real-world constraints limit access to targeted options. The case underscores the value of integrating molecular diagnostics early, particularly in patients likely to benefit from targeted agents.

Conclusion When clinical and biochemical indicators are incongruent, comprehensive IHC can guide accurate diagnosis. In advanced lung adenocarcinoma, especially in non-smokers, early molecular profiling is essential. This case exemplifies the importance of timely, integrated diagnostics to inform optimal, individualized care.

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