Indeterminate Thyroid Cytology Cases with BRAF Mutations – Underlying Cytologic, Molecular, and Pathologic Characteristics
Rashi Singhal, Marina N Nikiforova, Karen E Schoedel, Yuri E Nikiforov, N Paul Ohori. University of Pittsburgh Medical Center-Presbyterian, Pittsburgh, PA
Background: Mutation in the BRAF gene is highly specific for papillary thyroid carcinoma (PTC) and has been found predominantly in classical and tall cell variant of PTC. Therefore, cytology specimens with BRAF mutation are expected to show typical cytologic features and diagnosed as PTC. However, the more significant value of BRAF mutational testing may be in its potential to contribute toward the diagnostic accuracy of indeterminate thyroid cytology cases. In this study, we investigated the characteristics of the indeterminate diagnoses with BRAF mutation.
Design: Cytology cases demonstrating BRAF mutation in PTCs were selected from our pathology files from April 2007 to July 2011. From this group, we identified cases with the diagnoses of Atypia of Undetermined Significance (AUS), Follicular Neoplasm (FN), and Suspicious for Malignancy (SM) according to the Bethesda System. Samples were collected prospectively for cytologic analysis and molecular studies (placed into nucleic acid preservative solution). BRAF mutational analyses were performed by the real time polymerase chain reaction (PCR) and post-PCR melting curve analysis. The indeterminate diagnoses were correlated with the cytologic features, BRAF mutational status, and surgical pathology outcome.
Results: One-hundred twenty-one (121) cases of BRAF mutated PTC were identified. Of these, 33 cases (27%) were associated with indeterminate diagnoses. The correlations were summarized in the table. The BRAF K601E mutation was present in 9 of 33 indeterminate cases, but none in the SM group. There were no tall cell variant PTC cases and the vast majority of classic PTCs were in the SM group.
|Indeterminate Diagnosis||Cytologic Features||BRAF mutational status||Surgical Pathology Outcome of PTC type|
|AUS (n=16)||-mild atypia (9), hypocellular with focal atypia (5), focal microfollicles (2)||V600E (10), K601E (6)||MC (5), FV (3), Solid (1), CL (1), NOS (1), No F/U (5)|
|FN (n=4)||-microfollicular pattern (4)||V600E (1), K601E (3)||FV (3), MC (1)|
|SM (n=13)||-significant atypia (13)||V600E (13), K601E (0)||CL (8), MC (2), Warthin-like (1), NOS (1), No F/U (1)|