Anaplastic Transformation of Thyroid Follicular Adenoma Driven by TP53 and TERT Promoter Mutations with Triple-Tissue Sequencing Evidence

Abstract Anaplastic thyroid carcinoma (ATC) is a highly lethal malignancy that usually arises from pre-existing differentiated thyroid cancers, but direct transformation from a benign follicular adenoma has rarely been documented at the molecular level. We report an 83-year-old woman who experienced rapid enlargement of a long-standing thyroid nodule. Whole-exome and targeted sequencing provide direct in vivo evidence of clonal evolution from a follicular adenoma to ATC. The coexistence of follicular thyroid adenoma and ATC within the same nodule is exceedingly rare and, to our knowledge, has not been previously documented at the molecular level. Histological examination of the resection specimen revealed two distinct but adjacent components within the same nodule: follicular adenoma and anaplastic carcinoma (squamous cell carcinoma). Immunohistochemistry demonstrated gradual dedifferentiation from adenoma to anaplastic carcinoma, characterized by the absence of expression of thyroglobulin, thyroid transcription factor-1 and PAX-8, loss of E-cadherin expression, a mutant-pattern p53 staining, and an increase in the Ki-67 labeling index from 5% in the adenoma to > 60% in the anaplastic carcinoma. The squamous component was diffusely positive for p40 and CK5/6. Whole exome sequencing and thyroid-specific 12-gene panel testing revealed that in addition to a shared HRAS mutation, the anaplastic carcinoma uniquely harbored a TP53 inactivating mutation and a TERT promoter activation mutation. These histological, immunohistochemical, and molecular genetic findings provide direct evidence that this case represents a direct transformation from follicular adenoma to anaplastic carcinoma.