MON-323 Transdifferentiation of Classic Papillary Thyroid Carcinoma to a High Grade Mucoepidermoid Carcinoma: A Case Report With Molecular Insights

Abstract Disclosure: R. Ghosh: None. F. Toloza Bonilla: None. G. Thota: None. H. Alkaissi: None. P. Veeraraghavan: None. S.R. Carr: None. J. Klubo-Gwiezdzinska: None. S. Gubbi: None. Background: Transdifferentiation of classic papillary thyroid carcinoma (cPTC) to more aggressive histological subtypes likely results from epithelial to mesenchymal transition (EMT) which involves modifications in transcription factors, signal transduction, epigenetics, and non-coding RNAs. Transformation of cPTC into mucoepidermoid carcinoma (MEC) is extremely rare, and the associated EMT events are poorly understood.1Clinical Case: A 62-year-old female with a history of radioiodine (RAI)-refractory cPTC status post total thyroidectomy and RAI therapy was referred to our center for evaluation of metastatic disease. Total thyroidectomy was performed 11 years ago followed by 150 mCi 131I RAI therapy under levothyroxine withdrawal with a post-therapy scan revealing thyroid bed uptake. Histopathology had shown multifocal cPTC (largest focus: 1.5 cm), with perithyroidal soft tissue extension, positive margins, and 0/1 perithyroidal lymph node involvement (pT3bN0M0). After disease stability for several years, an increase in anti-thyroglobulin (Tg) antibodies with undetectable serum Tg was noted one year ago. The 123I diagnostic scan was unrevealing, but an 18-fluorodeoxyglucose positron emission tomography-computed tomogram (18FDG PET/CT) demonstrated an avid thyroid bed lesion and numerous, avid pulmonary nodules. Further evaluation at our center with a CT scan revealed progressive pulmonary metastatic disease, along with bulky mediastinal adenopathy and a new 3.1 cm x 2.7 cm peripancreatic mass. Due to concerns of a non-thyroid malignancy, a biopsy of the peripancreatic mass, and 4 lung nodules was performed. Histopathology of the peripancreatic mass and 2/4 lung masses revealed a high-grade MEC with areas of squamous carcinoma, adenocarcinoma, and anaplastic carcinoma, while the other 2 lung nodules were cPTC. Interestingly, the immunohistochemistry of MEC, while negative for TTF-1 and Tg, was positive for PAX-8, suggesting a thyroid origin. Furthermore, molecular testing revealed BRAF V600E (c.1799T>A) and TERT (c.-124C>T) pathogenic variants (PVs) in both cPTC and MEC tumors. In the MEC component, there were additional PVs in ARID2 (c.1716-1G>A and c.2710C>T), TP53 (c.574C>T), NOTCH2 (c.846C>G), and PIK3CB (c.3199G>C). Dabrafenib and trametinib therapy initially resulted in partial response but soon afterwards, the disease rapidly progressed, and the patient unfortunately succumbed to the disease. Conclusion: We describe the potential molecular mechanisms of EMT that may have transformed a cPTC to a high-grade MEC due to PVs in genes involved in chromatin remodeling (ARID2) and signal transduction (NOTCH2 and PIK3CB). This may have led to aberrant histopathological differentiation, as in this patient, who clinically manifested RAI-refractoriness and rapidly progressive disease. 1. Reference: Baloch et al. Endocrine pathology 33.1 (2022): 27-63. Presentation: Monday, July 14, 2025