Ovarian Clear Cell Carcinoma and Markers of Epithelial-Mesenchymal Transition (EMT): Immunohistochemical Characterization of Tumor Budding

Abstract

Tumor budding, largely considered a manifestation of epithelial-mesenchymal transition (EMT) is an established prognostic marker for several cancers. In a recent study, tumor budding was associated with poor clinical outcomes in early-stage ovarian clear cell carcinoma. Here, we evaluated the immune expression of 3 proteins shown to be associated with EMT (E-cadherin, β-catenin, and glypican-3) in 72 primary tumors of ovarian clear cell carcinoma with median follow-up of 39.47 mo. E-cadherin and β-catenin expression was further evaluated in tumor buds in 29 (40%) cases. In the tumor mass, diffuse membranous expression of E-cadherin and β-catenin was seen in 83% (60/72) and 81% (58/72) cases, respectively. Nuclear accumulation of E-cadherin was seen in 7 (10%) cases, while none of the cases showed nuclear β-catenin expression. Glypican-3 expression was diffuse in 33.3% (24/72), patchy in 29.2% (21/72), and absent in 37.5% (27/72) cases. Evaluation of tumor buds showed aberrant patterns of expression (complete loss/cytoplasmic accumulation/diminished, discontinuous incomplete membranous staining) of E-cadherin in 29/29 (100%) and of β-catenin in 26/29 (90%) cases. E-cadherin, β-catenin, and glypican-3 expression in the main tumor mass had no association with stage, lymph node status, recurrent/progressive disease, status at last follow-up, survival and histopathologic features (P>0.05). Our finding of aberrant expression of both E-cadherin and β-catenin in tumor buds indicates involvement of Wnt signaling pathway/EMT in tumor budding and outlines its significance as a prognostic marker especially for early-stage ovarian clear cell carcinoma.