Diagnostic and management in a rare case of double primary carcinoma: metastatic papillary thyroid cancer coexisting with TTF-1/p40 co-expressing non-small cell lung cancer

Multiple primary cancers (MPC) involving both thyroid and lung are diagnostically challenging. The co-expression of TTF-1 and p40 in non-small cell lung cancer (NSCLC) defines a rare, aggressive subtype. Distinguishing between metastatic thyroid cancer and a second primary lung cancer, especially with overlapping features, is crucial for appropriate management. We report a 70-year-old female with a history of papillary thyroid carcinoma (PTC) who developed multiple lung nodules. Initial biopsies confirmed a primary TTF-1/p40 co-expressing NSCLC, initially staged as metastatic lung cancer. Serial TGAb > 4000 IU/mL persisting despite I-131, with discordant radiologic response between unilateral right lower lobe lesion and bilateral nodules, served as the clinical clue prompting re-classification. Subsequent multidisciplinary review led to the revised diagnosis of MPC: metastatic PTC alongside a synchronous TTF-1/p40 co-expressing NSCLC. Following several lines of treatment, the patient received anlotinib combined with a PD-L1 inhibitor (sintilimab), which was associated with tumor regression enabling subsequent surgical resection of the lung cancer. Post-operatively, she continued this regimen with sustained disease control. This case underscores the diagnostic pitfalls in differentiating MPC from solitary metastatic disease. It highlights the critical role of integrated clinicopathological correlation, serial biomarker assessment, and multidisciplinary discussion in achieving an accurate diagnosis, which is the cornerstone for personalized treatment strategies in complex oncological cases. The experience suggests that combined anti-angiogenic and immunotherapy may have a role in rendering selected complex cases resectable, although this requires further investigation.