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Whole Slide Imaging Versus Microscopy for Primary Diagnosis in Surgical Pathology: A Multicenter Blinded Randomized Noninferiority Study of 1992 Cases (Pivotal Study)

Mukhopadhyay, Sanjay MD*; Feldman, Michael D. MD, PhD; Abels, Esther MSc; Ashfaq, Raheela MD, MS§; Beltaifa, Senda MD; Cacciabeve, Nicolas G. MD; Cathro, Helen P. MBChB, MPH; Cheng, Liang MD#; Cooper, Kumarasen MBChB, DPhil, FRCPath; Dickey, Glenn E. MD; Gill, Ryan M. MD, PhD**; Heaton, Robert P. Jr MD; Kerstens, René MSc; Lindberg, Guy M. MD§; Malhotra, Reenu K. MD§; Mandell, James W. MD, PhD; Manlucu, Ellen D. MD; Mills, Anne M. MD; Mills, Stacey E. MD; Moskaluk, Christopher A. MD, PhD; Nelis, Mischa MSc; Patil, Deepa T. MD*; Przybycin, Christopher G. MD*; Reynolds, Jordan P. MD*; Rubin, Brian P. MD, PhD*; Saboorian, Mohammad H. MD§; Salicru, Mauricio MD§; Samols, Mark A. MD, PhD; Sturgis, Charles D. MD*; Turner, Kevin O. DO§; Wick, Mark R. MD; Yoon, Ji Y. MD§; Zhao, Po MD, PhD; Taylor, Clive R. MD, PhD††

The American Journal of Surgical Pathology: January 2018 - Volume 42 - Issue 1 - p 39–52
doi: 10.1097/PAS.0000000000000948
Original Articles

Most prior studies of primary diagnosis in surgical pathology using whole slide imaging (WSI) versus microscopy have focused on specific organ systems or included relatively few cases. The objective of this study was to demonstrate that WSI is noninferior to microscopy for primary diagnosis in surgical pathology. A blinded randomized noninferiority study was conducted across the entire range of surgical pathology cases (biopsies and resections, including hematoxylin and eosin, immunohistochemistry, and special stains) from 4 institutions using the original sign-out diagnosis (baseline diagnosis) as the reference standard. Cases were scanned, converted to WSI and randomized. Sixteen pathologists interpreted cases by microscopy or WSI, followed by a wash-out period of ≥4 weeks, after which cases were read by the same observers using the other modality. Major discordances were identified by an adjudication panel, and the differences between major discordance rates for both microscopy (against the reference standard) and WSI (against the reference standard) were calculated. A total of 1992 cases were included, resulting in 15,925 reads. The major discordance rate with the reference standard diagnosis was 4.9% for WSI and 4.6% for microscopy. The difference between major discordance rates for microscopy and WSI was 0.4% (95% confidence interval, −0.30% to 1.01%). The difference in major discordance rates for WSI and microscopy was highest in endocrine pathology (1.8%), neoplastic kidney pathology (1.5%), urinary bladder pathology (1.3%), and gynecologic pathology (1.2%). Detailed analysis of these cases revealed no instances where interpretation by WSI was consistently inaccurate compared with microscopy for multiple observers. We conclude that WSI is noninferior to microscopy for primary diagnosis in surgical pathology, including biopsies and resections stained with hematoxylin and eosin, immunohistochemistry and special stains. This conclusion is valid across a wide variety of organ systems and specimen types.

*Department of Pathology, Cleveland Clinic, Cleveland, OH

Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia, PA

Philips Digital Pathology Solutions, Best, The Netherlands

§Miraca Life Sciences, Irving, TX

Advanced Pathology Associates, Silver Spring, MD

Department of Pathology, University of Virginia, Charlottesville, VA

#Department of Pathology, Indiana University School of Medicine, Indianapolis, IA

**Department of Pathology, University of California, San Francisco

††Department of Pathology, Keck School of Medicine University of Southern California, Los Angeles, CA

An abstract based on this study was presented (poster presentation) at the 2017 United States and Canadian Academy of Pathology (USCAP) Annual Meeting, San Antonio, TX.

Conflicts of Interest and Source of Funding: Supported by Philips. E.A., R.K., and M.N. are employees of Philips. C.R.T. and M.D.F. are consultants to Philips for which they receive a personal remuneration. S.M., D.T.P., C.G.P., and C.D.S. received a personal remuneration for participating as readers in this study and have no other relationships with or financial interest in Philips. A.M.M., C.A.M., J.W.M., S.E.M., and H.P.C. report that they received compensation in the form of salary support from Philips for their participation in this study. All pathologists in the study completed a Financial Disclosure Form and Form FDA 3454. The remaining authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Clive R. Taylor, MD, PhD, Department of Pathology, Keck School of Medicine University of Southern California, Pathology, HMR 311, Los Angeles, CA 90033 (e-mail:

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