Synchronous endometrial and minor salivary gland carcinomas – role of molecular diagnostics amid lack of clinical suspicion

Abstract Introduction/Objective Synchronous malignancies account for 3-5% of all tumor diagnoses but can be challenging to detect if one or both tumors are rare histologic subtypes and clinical suspicion is lacking. Molecular diagnostics are critical for accurate diagnosis in these difficult cases to guide appropriate patient care. Methods/Case Report We report the case of a 49-year-old female who was diagnosed with a high-grade, mixed- histology endometrial adenocarcinoma a few years back. She was found to have hilar and mediastinal nodal carcinoma of uncertain differentiation a couple of months after her initial diagnosis, clinically labelled as metastatic endometrial carcinoma. Following neoadjuvant chemotherapy, her hysterectomy showed complete pathologic response, and was found to be POLE ultramutated on NGS. Follow-up PET scan in 2023 showed progression of hilar/endobronchial thickening, as well as interval increase in size of mediastinal nodes, again presumed to be endometrial metastases, despite the POLE mutant status. Repeat sampling was performed from both the sites, along with comprehensive molecular profiling. Cytology from the nodes and surgical pathology from the endobronchial lesion showed similar morphology consisting of hyperchromatic basaloid cells in cribriform arrangement with tubular structures containing myxoid stromal material, negative for PAX-8, ER, p40, and TTF1 immunostains, inconsistent with endometrial metastasis. Molecular studies including FISH and NGS showed MYB1::NFIB fusion characteristic of adenoid cystic carcinoma and absence of POLE mutation, definitively refuting the clinically suspected progression of endometrial metastasis. Molecular testing confirmed that the endobronchial tumor and mediastinal nodal involvement were caused by a second primary, distinct from her POLE-ultramutated endometrial carcinoma which disappeared with chemotherapy. Her extended molecular workup also revealed a pathogenic mutation in BRIP1, suggesting a genetic cancer predisposition syndrome requiring referral for genetic counseling. Results (if a Case Study enter NA) NA Conclusion Molecular pathology is an invaluable tool for unravelling diagnostic complexity. Pathologists must integrate cytomorphology, molecular genetics and knowledge of cancer biology to steer the clinical teams towards the best patient care.