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

Abstract 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.

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Journal
Research Square
Published
2026-11-01
DOI
https://doi.org/10.21203/rs.3.rs-11260893/v1
Primary Topic
Neuroendocrine Tumor Research Advances
Type
preprint

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preprint

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

Katja Steiger, Konrad Steinestel, Anne‐Sophie Litmeyer, Bruno Märkl et al.
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Research Square
Neuroendocrine Tumor Research Advances
preprint

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

Katja Steiger, Konrad Steinestel, Anne‐Sophie Litmeyer, Bruno Märkl, Hanibal Bohnenberger, Moritz Jesinghaus, Carsten Denkert, Daniel‐Christoph Wagner, Alexander Quaas, Atsuko Kasajima, Sebastian Foersch, Markus Eckstein, Günter Klöppel, Detlef Klaus Bartsch, Marcus Kremer, Philipp Stroebel, Maxime Philipp Schmitt, Matthias Evert, Katharina Ofner
preprint en

Abstract

Abstract 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.

Research Square
Philipps University of Marburg (DE), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), University Hospital Augsburg (DE), Universitätsklinikum Erlangen (DE), University Medical Center of the Johannes Gutenberg University Mainz (DE), Universitätsmedizin Göttingen (DE), München Klinik (DE), University Hospital Cologne (DE), Bundeswehrkrankenhaus Ulm (DE), University of Regensburg (DE), Technical University of Munich (DE)
Amgen, Bristol-Myers Squibb, AstraZeneca, Sanofi, Gilead Sciences, Genomic Health, Wilhelm Sander-Stiftung, Merck KGaA, Universitätsmedizin Göttingen, Bundesministerium für Bildung und Forschung, Eisai, Astellas Pharma, Deutsche Krebshilfe, Ipsen, Novartis Pharma, Daiichi Sankyo Europe
Good health and well-being
Neuroendocrine Tumor Research Advances
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