Molecular correlates and nuclear features of encapsulated follicular-patterned thyroid neoplasms

Background: Assessing nuclear features is diagnostically challenging in the aspect of thyroid pathology. The aim of this study was to determine whether pathologists could distinguish BRAF-like and RAS-like nuclear features morphologically and identify morphological features to differentiate thyroid tumors with RAS-like mutations from encapsulated papillary thyroid carcinoma (PTC) with predominant follicular growth and BRAF^V600E mutation. Methods: Representative whole slide images of 16 encapsulated thyroid tumors with predominant follicular growth were reviewed by 12 thyroid pathologists using a web browser-based image viewer. Total nuclear score was calculated from semi-quantitatively scored eight nuclear features. The molecular profile of RAS and BRAF genes was determined by Sanger sequencing. Results: Total nuclear score ranging 0 to 24 could differentiate BRAF-like tumors from RAS-like tumors with a cut-off value of score 14. The interobserver agreement was the highest for the assessment of nuclear pseudoinclusions (NPIs) but the lowest for nuclear elongation and sickle-shaped nuclei. NPIs were found in tumors with BRAF^V600E mutation, but not in tumors with RAS-like mutations. Total nuclear scores were significantly higher for tumors with BRAF^V600E than for those with RAS-like mutations (P<0.001). Conclusion: Our results suggest that NPIs and high nuclear scores have diagnostic utility as rule-in markers for differentiating PTC with BRAF^V600E mutation from benign or borderline follicular tumors with RAS-like mutations. Relaxation of rigid criteria for nuclear features resulted in an overdiagnosis of PTC. Immunostaining or molecular testing for BRAF^V600E mutation is a useful adjunct for cases with high nuclear scores to identify true PTC.