Semi-quantitative Assessment of Cytomorphologic Features Can Predict Mutation Status of Thyroid Nodules with Indeterminate Cytologic Diagnosis

Molecular diagnostics increasingly direct the management of thyroid nodules with an indeterminate cytologic diagnosis. This study was undertaken to correlate cytomorphologic features with the molecular profiles in an effort to identify features predictive of molecular aberrations. 189 thyroid nodules with an indeterminate thyroid cytology diagnosis (atypia of undetermined significance, suspicious for follicular lesion, and suspicious for malignancy) with an adequate sample submitted for targeted mutation detection by PCR or next generation sequencing (NGS) were assessed semi-quantitatively for following cytomorphologic parameters: (cellularity, Hurthle cell changes, microfollicles, nuclear elongation, nuclear grooves, nuclear enlargement , nuclear atypia, extent of atypia and colloid). Based on this evaluation, a cumulative cytomorphologic score (CCS) and a more simplified overall atypia score (OAS) were assigned to each case. Associations among mutational status and each of the aforementioned parameters, CCS and OAS scores were determined. Of the 189 nodules with indeterminate cytology, 63 (33.3%) harbored at least one mutation. RAS and BRAF were the most common mutations, found in 34 (18.0%) and 13 (6.9%) cases respectively. Both CCS and OAS were highly associated with the presence of all mutations (p<0.0001) and with the presence of BRAF and RAS mutations in particular (all p <0.01). Semi-quantitative assessment of various cytomorphologic features in indeterminate thyroid cytology cases showed a strong association of higher OAS and CCS scores and incidence of BRAF and RAS mutations. Utilizing a more objective approach to thyroid cytology can potentially decrease the overall number of indeterminate diagnoses leading to fewer repeat procedures and unnecessary surgeries.