Clear Cell Change in Thyroid Carcinoma: A Clinicopathologic and Molecular Study with Identification of Variable Genetic Anomalies

Background: Clear-cell carcinoma of the thyroid has been regarded as a variant of follicular (FTC) or papillary (PTC) thyroid carcinoma. Twenty-one primary thyroid carcinomas with clear-cell features, diagnosed in 20 patients (12 female) were identified between 1992 and 2012 (0.5% of in-house thyroid carcinomas). Methods: Hematoxylin and eosin slides were reviewed. SNaPshot multigene mutational analysis and a translocation panel were successfully performed on 15 of these cases. Results: Twelve (57%) were FTC, five were conventional PTC, two were follicular variant of PTC, and two were poorly differentiated thyroid carcinomas. Five cases had RAS mutation (four FTC and one PTC); two had PAX8-PPARgamma translocations (both FTC, one with concurrent p53 mutation); one had an EML4-ALK translocation (PTC); and one had a TFG-MET translocation (follicular variant of PTC). Five carcinomas were metastatic to regional lymph nodes (three FTC and two PTC), and two were metastatic to bone (both FTC). Disease confined to the thyroid (67%) and rates of regional lymph node metastasis (24%) and distant metastasis (10%) were near the national averages (68%, 25%, and 5%, respectively). One patient with a poorly differentiated thyroid carcinoma died one year after diagnosis, and a patient with metastatic FTC died two years after diagnosis. Overall mortality was 10%. Conclusions: Clear-cell change in thyroid carcinoma is rare, is more common in FTC than it is in PTC, is found focally or multifocally within a given lesion, and is frequently associated with RAS mutations (33%). Clear-cell change in thyroid neoplasia should raise the possibility of follicular carcinoma, and should not be treated differently from other carcinomas of similar grade and stage.