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Ovarian Carcinoma Histotype

Strengths and Limitations of Integrating Morphology With Immunohistochemical Predictions

Köbel, Martin, M.D.; Luo, Li, Ph.D.; Grevers, Xin, M.Sc.; Lee, Sandra, M.D.; Brooks-Wilson, Angela, Ph.D.; Gilks, C. Blake, M.D.; Le, Nhu D., Ph.D.; Cook, Linda S., Ph.D.

International Journal of Gynecological Pathology: July 2019 - Volume 38 - Issue 4 - p 353–362
doi: 10.1097/PGP.0000000000000530

Ovarian carcinoma histotypes are critical for research and patient management and currently assigned by a combination of histomorphology +/− ancillary immunohistochemistry (IHC). We aimed to validate the previously described IHC algorithm (Calculator of Ovarian carcinoma Subtype/histotype Probability version 3, COSPv3) in an independent population-based cohort, and to identify problem areas for IHC predictions. Histotype was abstracted from cancer registries for eligible ovarian carcinoma cases diagnosed from 2002 to 2011 in Alberta and British Columbia, Canada. Slides were reviewed according to World Health Organization 2014 criteria, tissue microarrays were stained with and scored for the 8 COSPv3 IHC markers, and COSPv3 histotype predictions were calculated. Discordant cases for review and COSPv3 prediction were arbitrated by integrating morphology with IHC results. The integrated histotype (N=880) was then used to identify areas of inferior COSPv3 performance. Review histotype and integrated histotype demonstrated 93% agreement suggesting that IHC information revises expert review in up to 7% of cases. There was also 93% agreement between COSPv3 prediction and integrated histotype. COSPv3 errors predominated in 4 areas: endometrioid carcinoma (EC) versus clear cell (N=23), EC versus low-grade serous (N=15), EC versus high-grade serous (N=11), and high-grade versus low-grade serous (N=6). Most problems were related to Napsin A-negative clear cell, WT1-positive EC, and p53 IHC wild-type high-grade serous carcinomas. Although 93% of COSPv3 prediction accuracy was validated, some histotyping required integration of morphology with ancillary test results. Awareness of these limitations will avoid overreliance on IHC and misclassification of histotypes for research and clinical management.

Departments of Pathology and Laboratory Medicine (M.K., S.L.)

Community Health Sciences (L.S.C.), University of Calgary

Department of Cancer Epidemiology and Prevention Research, Alberta Health Services-Cancer Control Alberta (X.G., L.S.C.), Calgary, Alberta

Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver; and Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby (A.B.-W.)

Department of Pathology and Laboratory Medicine, University of British Columbia (C.B.G.)

Cancer Control Research, BC Cancer Research Centre (N.D.L.), Vancouver, British Columbia, Canada

Department of Internal Medicine, Division of Epidemiology, Biostatistics and Preventive Medicine, UNM Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico (L.L., L.S.C.)

M.K., L.S.C.: conception and design. A.B.-W, N.D.L., L.S.C.: provision of study material or patients. M.K., S.L., C.B.G., X.G.: collection and assembly of data. L.L., M.K., L.S.C.: data analysis and interpretation. M.K., X.G., L.S.C.: manuscript drafting.

Supported by the Cancer Research Society (19319) and CLS internal research support RS11-508. Tissue sample collection of OVAL-BC cohort was supported by National Institutes of Health Cancer Support Grant 2 P30 CA118100-11.

The authors declare no conflict of interest.

Address correspondence and reprint requests to Martin Köbel, MD, Department of Pathology and Laboratory Medicine, University of Calgary, #7564—1403 29th St. NW, Foothill Medical Center, Calgary, AB, Canada T2N 2T9. E-mail:

©2019International Society of Gynecological Pathologists