Multifocal papillary thyroid carcinoma with RET p.V804M, EML4-ALK fusion, and BRAF V600E positivity

Multifocal papillary thyroid cancer (PTC) can arise from independent primaries with discordant drivers in parallel clonal evolution rather than a single-clone pattern. We present a 31-year-old female with multifocal PTC harboring 3 distinct oncogenic alterations: a germline RET p.V804M mutation, low-frequency EML4-ALK fusion, and BRAF V600E mutation. The RET and ALK alterations were identified in a midpole nodule, whereas BRAF positivity was seen in a separate lower pole tumor. Ultrasound revealed multiple right-lobe thyroid nodules; the dominant 2.1-cm lesion was hypoechoic with calcifications. Fine needle aspiration revealed Bethesda III cytology, prompting thyroid lobectomy and an ipsilateral central neck dissection was performed. Histopathology confirmed multifocal PTC and a background of chronic lymphocytic thyroiditis with 23 lymph nodes negative for metastasis. This case presents heterogeneity of oncogenic drivers in PTC and the potential value of comprehensive molecular profiling in risk stratification and management.