Tall Cell Variant of Papillary Thyroid Carcinoma: Impact of Change in WHO Definition and Molecular Analysis

The morphologic criteria for tall cell variant (TCV) of papillary thyroid carcinoma (PTC) were modified in the 2017 WHO Classification of Tumors of Endocrine Organs, with a decrease in the requirements for both the height of cells and in the percentage of tumor demonstrating a tall cell morphology. The aim of this study was to determine if the change in criteria would result in a significant increase in the percentage of tumors that meet criteria for TCV. In addition, we evaluated the correlation between morphology, molecular alterations, and clinical behavior of TCV. We studied three cohorts to evaluate the above stated questions. The first cohort was comprised of 97 PTC consecutively resected over a 12-month period that were originally diagnosed as classic PTC, PTC with tall cell features, or TCV. Tumor slides of each case were reviewed to determine the percentage of the tall cell component (<30%, 30-49%, and >50%) and the height of the cells in this component. This cohort was evaluated to determine if the change in WHO criteria would result in a significant increase in the percentage of tumors that meet criteria for TCV. Our second cohort consisted of nine consecutively resected PTC with a tall cell component >30% (with tall cells defined as at least 2-3x as tall as wide) that had molecular characterization through a targeted, next-generation sequencing (NGS) assay. The molecular characteristics were correlated with the percentage of the tall cell component. Finally, a third cohort comprised of seven clinically aggressive TCV (defined as those with T4 disease, disease recurrence, or subsequent tumor dedifferentiation) was evaluated to determine histologic and molecular characteristics. In cohort 1, the number of cases classified as TCV increased significantly with the change in definition of TCV: 8 (8%) cases met the previous criteria for TCV (cells 3x as tall as wide in >50% of the tumor), whereas 24 (25%) cases met the new 2017 WHO criteria (cells 2-3x as tall as wide in >30% of the tumor) (p=0.0020). Molecular analysis of cohort 2 revealed that all 9 cases harbored a BRAF V600E mutation. Pathogenic secondary mutations were absent in cases with <50% tall cells, but they were detected in 2 (33%) of 6 cases with >50% tall cells (2 cases with TERT promoter mutations, including 1 that also had an AKT2 mutation). Histologic and molecular analysis of the clinically aggressive cohort (cohort 3), revealed that all cases had >50% tall cells and 3 (43%) had secondary oncogenic mutations (all TERT promoter mutations). We found that the modified morphologic criteria put forth in the 2017 WHO tripled the number of cases that would be classified as TCV. Moreover, clinically aggressive tumors and those harboring secondary oncogenic mutations all had a tall cell component >50%. Additional large multi-institutional studies incorporating clinical outcome and molecular data would be valuable to determine the best histologic definition of TCV.