To subdivide large cohorts into meaningful risk groups, we demonstrate that a two-tiered system that defines high-grade MTCs as tumors with at least one of the following three features: MI ≥ 5 per 2 mm2, Ki67 proliferative index ≥ 5%, and/or tumor necrosis, identifies MTCs with a profoundly greater risk of progressive and fatal disease. This evidence concerns the gene MKI67 and neoplasm.