Stains & CD markers
EZH2

Editorial Board Member: Christian M. Schürch, M.D., Ph.D.
Editor-in-Chief: Debra L. Zynger, M.D.
Laseena Vaisyambath, M.B.B.S.
Raavi Gupta, M.D.

Last author update: 8 February 2023
Last staff update: 8 February 2023

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PubMed Search: EZH2

Laseena Vaisyambath, M.B.B.S.
Raavi Gupta, M.D.
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Cite this page: Vaisyambath L, Xia R, Gupta R. EZH2. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainsEZH2.html. Accessed February 23rd, 2024.
Definition / general
Essential features
Terminology
  • Enhancer of zeste 2 polycomb repressive complex 2 subunit
Pathophysiology
  • EZH2 is a member of polycomb group family and polycomb repressive complex 2 (PRC2) is 1 of the 2 PcG protein core complexes that mediate gene silencing
  • Catalyzes the trimethylation of histone 3 lysine 27 (H3K27me3), associated with transcriptional repression
    • Further suppresses the activity of genes related to stem cell differentiation and ablates normal development (Nat Med 2016;22:128)
  • PRC2 methylates nonhistone protein substrates, including the transcription factor GATA4; EZH2 also directly interacts with other proteins to activate downstream genes in a PRC2 independent manner (J Hematol Oncol 2020;13:104)
  • Gain of function mutations or EZH2 overexpression is associated with non-Hodgkin lymphoma, squamous cell carcinoma, malignant liver neoplasm and melanoma (Clin Cancer Res 2011;17:2613)
  • Gain of function mutations or EZH2 overexpression is associated with worse progression of prostate cancer, breast cancer, bladder cancer, endometrial cancer, myelodysplastic syndromes and melanoma (Nat Med 2016;22:128)
  • Loss of function mutations are associated with a subset of myelodysplastic syndromes / myeloproliferative neoplasms and T cell acute lymphoblastic leukemia (Nat Med 2016;22:128)
  • Overexpression is associated with chronic myeloid leukemia (CML) (Cells 2020;9:1639)
  • Potential therapeutic target; 2 phase II trials of EZH2 inhibitors for treating lymphoma are underway (Nat Med 2016;22:128)
  • P53 may be a target gene for EZH2 and inhibition of p53 expression might lead to the development of ovarian cancer (Int J Clin Exp Pathol 2020;13:456)
Diagrams / tables

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EZH2 as a repressor

Pathophysiology of EZH2 and its role in carcinomas

Interpretation
  • Nuclear staining
Uses by pathologists
  • Differentiates malignant effusions (MOC31 membranous and EZH2 nuclear staining) from benign effusions (Diagn Cytopathol 2017;45:118, Diagn Cytopathol 2014;42:111)
  • Differentiates malignant mesothelioma (loss of BAP1 and high expression of EZH2) from benign mesothelial proliferation (Histopathology 2017;70:722)
  • Differentiates squamous cell carcinoma (> 35% staining) from normal skin (< 5% staining) and actinic keratosis (< 15% staining) (Eur J Dermatol 2014;24:41)
  • Differentiates cholangiocarcinoma (positive) from ductular reaction and bile duct adenoma (negative) (Am J Surg Pathol 2014;38:364)
  • Differentiates invasive high grade urothelial carcinoma (high intensity and percentage in staining) of the bladder from noninvasive low grade urothelial carcinoma and carcinoma in situ (low intensity and percentage in staining) (Urol Oncol 2012;30:428)
  • Differentiates malignant (positive) from benign (negative) hepatic tumors (Diagn Pathol 2012;7:86)
  • Differentiates ovarian cancer (significantly higher) from borderline, benign and normal group (Int J Clin Exp Pathol 2020;13:456)
  • Differentiates well differentiated leiomyosarcoma from cellular leiomyoma and well differentiated embryonal rhabdomyosarcoma from fetal rhabdomyoma (Sci Rep 2018;8:12331)
Prognostic factors
Microscopic (histologic) description
  • Scattered nuclear staining in the basal layer of the benign epithelium of the gastrointestinal tract, bronchus, endometrium and skin
  • Increased intensity of staining and number of positive cells in invasive squamous cell carcinoma, adenocarcinoma of the colorectum, urothelial carcinoma, renal cell carcinoma, NK / T cell lymphoma and high grade neuroendocrine tumor
  • EZH2 shows increased expression in cytoplasm and nucleus, while mutated P53 shows expression mainly in nucleus in ovarian carcinoma (Int J Clin Exp Pathol 2020;13:456)
Microscopic (histologic) images

Contributed by Raavi Gupta, M.D.

Low grade neuroendocrine tumor

High grade neuroendocrine tumor


Normal skin

Squamous cell carcinoma in situ

Squamous cell carcinoma

Positive staining - normal
  • Testis, placenta, bone marrow: diffuse and strong staining
  • Skin: scattered and weak staining in the basal and spinous layer of the epidermis and strong intense stain in Langerhans cells (Eur J Dermatol 2014;24:41)
  • Esophagus, vagina, cervix: scanty and weak staining in the basal layer of the squamous epithelium
  • Gastrointestinal tract, fallopian tube, endometrium: scattered and weak staining in the basal layer of the epithelium and deep crypts
Positive staining - disease
Negative staining
Sample pathology report
  • Effusion fluid, abdomen:
    • Positive for malignancy (see comment)
    • Comment: Clusters of epithelial cells with hyperchromatic and angulated nuclei present in both ThinPrep and cell block. Immunohistochemical stains performed on sections of cell block show that tumor cells are positive for MOC31 and PAX8, while negative for D2-40 and calretinin. EZH2 stain is strongly positive in around 70% of tumor cells. These findings are consistent with metastatic adenocarcinoma of Müllerian primary.
Board review style question #1
A 56 year old woman reports cough, fatigue and low fever for 3 months, which has worsened in the past 2 days. She is admitted to the emergency room. Chest Xray shows opacity in the right upper lobe and extensive effusion in the right lung. Thoracentesis reveals tan-yellow fluid containing scanty clusters of epithelioid cells forming 3 dimensional architecture, with slightly enlarged nuclei and prominent nucleoli in the background of extensive inflammation, neutrophil infiltration and degenerative changes. Which of the following immunostains support the diagnosis of a malignant effusion over a benign effusion in the cell block?

  1. MOC31 membranous and EZH2 membranous staining
  2. MOC31 membranous and EZH2 nuclear staining
  3. MOC31 negative and EZH2 cytoplasmic staining
  4. MOC31 nuclear and EZH2 cytoplasmic staining
Board review style answer #1
B. MOC31 membranous and EZH2 nuclear staining supports the diagnosis of malignant effusion over benign effusion.

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