Objectives
Medullary thyroid carcinoma (MTC) is an aggressive neuroendocrine tumor (NET) that arises from calcitonin-producing C cells. Unlike other NETs, there is no widely accepted pathologic grading system. In 2022, the WHO recommendations for the classification of thyroid neoplasms used proliferative activity (mitotic index and/or Ki67 proliferation index) and tumor necrosis as criteria. Based on the newly applied WHO grading system recommendations for MTC, we analyzed the pathology slides of medullary carcinoma from a Korean clinical institution by grade and compared them with actual prognosis to check the validity and usefulness of the recommendations.

Methods
From August 2005 to August 2023, tumor specimens from 167 MTC patients at Severance Hospital in Seoul, Korea, were reviewed for mitotic activity, Ki67 proliferation index, presence of necrosis, and other clinicopathologic features according to uniform criteria, and medical records were retrospectively analyzed. After pathologic analysis, they were divided into a two-grade system, and high-grade medullary carcinoma was defined as having at least one of the following features : Mitotic index ≥ 5 per 2 mm2, Ki67 proliferation index ≥ 5% and/or tumor necrosis

Results
Twenty-nine (17.4%) MTCs were highly graded using this approach. In univariate analysis, these patients had a significantly higher risk of overall (hazard ratio [HR] 8.636; 95% CI, 2.967 to 25.134; P, < .001), disease-specific (HR 14. 521; 95% CI, 2.807 to 75.119; P , 0.0014), distant metastasis-free (HR 2.245; 95% CI, 0.23 to 21.949; P, 0.487), and locoregional recurrence-free (HR 8.914; 95% CI, 3.186 to 24.942; P, <0.001) survival.

Conclusions

In this study, the validity and usefulness of the two-stage international grading system for prognostic analysis of MTC was confirmed. Therefore, we recommend grading MTC based on mitotic count, Ki67 proliferation index, and tumor necrosis.