The Diagnostic Value of EZH2 in Distinguishing NET G3 from NEC: An Immunohistochemical Study of 1618 Neuroendocrine Neoplasms of Various Origins and Grades

The distinction between well-differentiated neuroendocrine tumours of grade 3 (NET G3) and poorly differentiated neuroendocrine carcinomas (NEC) guides treatment but remains challenging. We evaluated Enhancer of Zeste Homolog 2 (EZH2) immunohistochemistry as a supportive marker in 1618 neuroendocrine neoplasms (NEN) from ten centres, including 1083 NET G1/G2 and pulmonary carcinoids, 56 NET G3, 443 NEC and 36 medullary thyroid carcinomas and pheochromocytomas/paragangliomas, using the H-score with three expression groups (low < 100, intermediate 100–200, high > 200). EZH2 expression was low in 99.2% of NET G1/G2 and carcinoids and in all medullary thyroid carcinomas and pheochromocytomas/paragangliomas. NET G3 were EZH2-low in 67.9%, intermediate in 23.2% and high in 8.9% of cases, whereas large and small cell NEC were high in 52.2%, intermediate in 34.0% and low in 13.8% (p < 0.001). Low EZH2 expression supported NET G3 with a specificity of 86.2% (positive likelihood ratio 4.9), high expression supported NEC with a specificity of 91.1% (positive likelihood ratio 5.8), and intermediate expression was non-discriminatory. In an exploratory subset, EZH2 and p53/RB1 immunohistochemistry provided complementary information. EZH2 expression was associated with overall survival across the cohort but not within NET G3 or NEC. EZH2 is a simple supportive marker for the distinction of NET G3 and NEC: low expression supports NET G3, high expression supports NEC, and intermediate expression should be resolved by morphology and the established markers.