Cytokeratin 5/6 expression, prognosis, and association with estrogen receptor α in high-grade serous ovarian carcinoma

Our plain-English summary of Cytokeratin 5/6 expression, prognosis, and association with estrogen receptor α in high-grade serous ovarian carcinoma, by E.T. Taube, C. Denkert, J. Sehouli, et al (Human Pathology, 2017).

The study

• Authors: E.T. Taube, C. Denkert, J. Sehouli, U. Unger, C.A. Kunze, J. Budczies, M. Dietel, E. Braicu, S. Darb-Esfahani
• Journal: Human Pathology
• Published: 2017;67:30-36
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

High-grade serous ovarian carcinoma remains one of the most lethal malignancies in women. For histopathologic differentiation from mesothelioma cytokeratin, 5/6 immunohistochemistry is widely used. Another preferred marker for differential diagnosis to mesothelioma is estrogen receptor α (ER-α). In this study, we determined the rate of cytokeratin 5/6-positive cells in primary high-grade serous carcinoma. A cohort of 215 patients with high-grade serous ovarian carcinoma was evaluated immunohistochemically for the protein expression of cytokeratin 5/6. Most tumors demonstrated at least partly positive for cytokeratin 5/6 (n=148; 68.3%), showing different staining patterns from scattered stained cells to a diffuse staining, at times with a distinctive tumor-stroma border motif. Sixty-seven (31%) were entirely negative. No correlation of cytokeratin immunoreactivity score (IRS) with conventional staging parameters could be demonstrated. From the different IRS values for cytokeratin 5/6, IRS=12 (n=6; 2.9%) seemed to indicate a worse prognosis, albeit not statistically significant. An association with ER-α expression could not be detected but the combination of cytokeratin 5/6 IRS=12 and ER-α negativity resulted in a significant negative prognostic marker (overall survival: P=.003 and progression-free survival: P<.0001). We substantiate cytokeratin 5/6 protein expression as a frequent feature of high-grade serous ovarian carcinoma with various staining patterns, an important fact for the routine differential diagnosis with mesothelioma. Furthermore, cytokeratin 5/6 in combination with ER-α proved to be a negative prognostic marker, wherefore we suggest further investigation of its biological significance and possible manifestation of a basal differentiation.

Copyright © 2017 Elsevier Inc. All rights reserved.

In plain English

This study examined cytokeratin 5/6, a protein marker pathologists use to tell high-grade serous ovarian carcinoma apart from mesothelioma. It did not study asbestos exposure. The authors stained tumor samples from 215 patients diagnosed at the Charité University Hospital in Berlin and scored staining from 0 (none) to 12 (strong staining in more than 80% of tumor cells). Some staining (scores 1 to 9) was seen in 142 cases (66.1%), 67 (31.2%) were entirely negative, and 6 (2.8%) scored 12. To rule out misclassified mesotheliomas, those six were stained for calretinin; all were negative. The cytokeratin 5/6 score alone was not significantly linked to stage or survival. For a score of 12, the hazard ratio was 1.77 (confidence interval 0.72-4.35). Grouping patients by a score of 12 and by estrogen receptor α status was significantly linked to survival (overall survival p=0.003), although only 2 patients had a score of 12 with estrogen receptor α staining below 10%. The authors concluded that cytokeratin 5/6 staining is frequent in this cancer and should be taken into account when distinguishing it from mesothelioma. They stated that the survival analysis was underpowered.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Immunohistochemical study of tumor tissue microarrays from a patient cohort, with analysis of links to clinical features and survival
• Who was studied: 215 patients with primary high-grade serous ovarian carcinoma diagnosed at the Institute of Pathology, Charité University Hospital, Berlin, Germany. 145 of them came from the Tumor Bank Ovarian Cancer project. Dates of diagnosis are not given.
• Exposure: No asbestos or other environmental exposure was studied. The factor examined was tumor staining for cytokeratin 5/6, scored by a semi-quantitative immunoreactivity score (IRS) from 0 to 12. It was examined alone and combined with estrogen receptor α (ER-α) status, which was split at 10% of stained tumor cells.
• Main results:
  • 142 of the tumors (66.1%) showed some cytokeratin 5/6 staining scored IRS 1 to 9.
  • 67 tumors (31.2%) were entirely negative for cytokeratin 5/6.
  • 6 tumors (2.8%) were entirely or nearly entirely positive with strong staining (IRS 12).
  • The six IRS 12 cases were re-checked to rule out misclassified mesotheliomas. All were negative for calretinin and had the typical appearance of high-grade serous adenocarcinoma.
  • Across the whole cohort, the cytokeratin 5/6 score showed no significant association with age 60 years or older, tumor stage (pT), node status (pN), FIGO stage, chemotherapy group or residual tumor.
  • The cytokeratin 5/6 score showed a borderline association with ER-α expression (p=0.087).
  • Across the whole cohort, the cytokeratin 5/6 score was not statistically associated with survival (overall survival p=0.571, progression-free survival p=0.366), and neither were selected cut-offs.
  • Patients with IRS 12 tumors had a hazard ratio of 1.77 (confidence interval 0.72-4.35). This was not statistically significant (overall survival p=0.207, progression-free survival p=0.382).
  • ER-α status was available for 208 patients. 138 (66.3%) had 10% or more stained tumor cells and 70 (33.7%) had less than 10%. Of the 6 IRS 12 patients, 4 were ER-α positive and 2 were ER-α negative.
  • Patients were split into four groups by cytokeratin 5/6 IRS 12 versus below 12 and by ER-α status. The groups were: ER-α below 10% with IRS below 12 (n=68); ER-α below 10% with IRS 12 (n=2); ER-α above 10% with IRS 12 (n=4); ER-α above 10% with IRS below 12 (n=133). This grouping was a significant prognostic marker (overall survival p=0.003; progression-free survival printed as p=0.000).
  • ER-α alone gave overall survival p=0.047 and progression-free survival p=0.147 (data not shown).
• The authors' conclusion: The authors concluded that cytokeratin 5/6 expression is a frequent feature of high-grade serous ovarian carcinoma. They said this should be taken into account when cytokeratin is used to distinguish this cancer from mesothelioma, and that a panel of mesothelial markers may clarify doubt. They also suggested further study of the biological significance of cytokeratin 5/6 expression and its relationship with ER-α.
• Limitations the authors state:
  • The authors said the study was underpowered for survival. About 595 events would have been needed to detect a hazard ratio of 2, but the study included 212 patients with 111 events. They said the prognostic value of cytokeratin 5/6 should be validated in larger independent cohorts.
  • The study was designed to describe staining for use in distinguishing these tumors from mesothelioma, not to study prognosis.
  • The authors said it is unknown what function, if any, cytokeratin 5/6 positive cells have in ovarian carcinoma.
  • The authors said very few patients fell into the combined ER-α and cytokeratin 5/6 subgroups, so they could not draw analogies with breast cancer.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Ovarian cancer.

Medical terms in this study, explained in our Lexicon: Cytokeratin 5/6, Prognosis, Carcinoma, Mesothelioma, Immunohistochemistry, Differential Diagnosis, Staging, Overall Survival.

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