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p53, Mismatch Repair Protein, and POLE Abnormalities in Ovarian Clear Cell Carcinoma

An Outcome-based Clinicopathologic Analysis

Parra-Herran, Carlos MD*,†; Bassiouny, Dina MD, PhD*,‡; Lerner-Ellis, Jordan MD, PhD†,§; Olkhov-Mitsel, Ekaterina PhD*; Ismiil, Nadia MBChB*,†; Hogen, Liat MD∥,¶; Vicus, Danielle MD, MSc∥,#; Nofech-Mozes, Sharon MD*,†

The American Journal of Surgical Pathology: December 2019 - Volume 43 - Issue 12 - p 1591–1599
doi: 10.1097/PAS.0000000000001328
Original Articles

The PROMISE diagnostic algorithm, which uses p53, mismatch repair (MMR) protein immunohistochemistry, and DNA polymerase ε (POLE) exonuclease domain mutation testing, is a reliable surrogate of the molecular group in endometrial carcinoma. Its prognostic value has been validated in endometrial carcinoma and ovarian endometrioid carcinoma. Moreover, a similar prognostic grouping has been recently documented in endometrial clear cell carcinoma. Thus, we aimed to explore the role of these markers in ovarian clear cell carcinoma, another endometriosis-associated malignancy. A total of 90 cases were identified and confirmed after secondary review. Immunohistochemistry for p53, MLH1, MSH2, MSH6, and PMS2 was performed in formalin-fixed, paraffin-embedded tissue. POLE mutational analysis was performed in 47 cases. Results were correlated with clinicopathologic variables including disease-free survival (DFS), overall survival, and disease-specific survival (DSS). Endometriosis was found in 67 (74%) cases. Six (7%) tumors were p53 abnormal, 82 (91%) were p53 normal, and 2 (2%) tumors had MMR deficiency (1 MSH6 loss and 1 MSH2/6 loss; both were p53 normal). Several POLE variants of unknown significance were detected, but no pathogenic mutations. The mean follow-up period was 43 months (median: 34, range: 1 to 189). Abnormal p53 status was associated with advanced Federation of Gynecology and Obstetrics stage, lymph node metastases, DFS and DSS (P<0.05, Fisher exact test). In univariate analysis, abnormal p53 and positive lymph node status had worse DFS, whereas bilaterality, surface involvement, and advanced stage were associated with worse DFS, overall survival and DSS (P<0.05, Cox regression). On multivariate analysis, only stage retained statistical association with survival. Using a molecular-based approach designed for endometrial carcinoma, most ovarian clear cell carcinomas fall into the copy-number-low molecular subgroup. However, a small but important subset has an abnormal p53 expression (copy-number-high group). This subset is associated with adverse features including extrapelvic disease, nodal metastases, and recurrence similar to endometrial and ovarian endometrioid cancer. Thus, testing for this marker has potential prognostic significance. The role of other markers in the PROMISE algorithm remains to be elucidated, as we found a low frequency of MMR abnormalities and no pathogenic POLE mutations in our series.

Departments of *Laboratory Medicine and Molecular Diagnostics

#Gynecologic Oncology, Sunnybrook Health Sciences Centre

Departments of Laboratory Medicine and Pathobiology

Obstetrics and Gynaecology, University of Toronto

§Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health System

Department of Gynecologic Oncology, University Health Network, Toronto, ON, Canada

Department of Pathology, Mansoura University, Mansoura, Egypt

Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Carlos Parra-Herran, MD, Department of Laboratory Medicine and Pathobiology, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Room E4-27a, Toronto, ON, Canada M4N 3M5 (e-mail:

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