Diagnostic Utility of Ki-67 Index on Cell Block Material for Grading Medullary Thyroid Carcinoma

An international grading system for medullary thyroid carcinoma (IMTCGS) was established in 2022. High-grade MTC is defined by the presence of one or more of the following features: mitotic index ≥ 5 per 2 mm², Ki-67 proliferative index ≥ 5%, or tumor necrosis. Fine-needle aspiration (FNA) is the primary diagnostic tool for MTC; however, tumor grading in cell blocks remains underexplored.

A total of 60 FNA cases diagnosed as MTC or metastatic MTC between 2000 and 2025 were identified. Of these, 15 met the inclusion criteria: cell blocks with > 500 tumor cells and corresponding surgical specimens available. The Ki-67 proliferation index was assessed in hotspot regions using an online platform.

The study included 11 adults and 4 pediatric/adolescents with a median age of 50 years (range: 8-76). Based on the IMTCGS grading criteria, six cases were classified as high-grade and nine as low-grade. In low-grade tumors, the Ki-67 proliferation index on surgical resections ranged from < 1% to 4%, and all corresponding cell blocks showed Ki-67 rates of ≤ 1%. High-grade tumors exhibited Ki-67 indices ranging from 7% to 24%, with mitotic figures ranging from 1 to 14 per 2 mm². Among these, two cell blocks showed Ki-67 rates of 5%, while the remaining four had rates between < 1% and 2%. Four of six patients with high-grade MTC developed distant metastases to the liver, lung, or bone, and one died of disease 35 months after diagnosis. None of the low-grade tumors developed distant metastasis.

Grading MTC using the Ki-67 proliferation index on cell blocks is challenging because of low cellularity and intratumoral heterogeneity in Ki-67 expression. In our study, this approach tended to undergrade high-grade MTC.