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Standardization of Negative Controls in Diagnostic Immunohistochemistry: Recommendations From the International Ad Hoc Expert Panel

Torlakovic, Emina E. MD, PhD*,†,‡; Francis, Glenn MBBS, FRCPA, MBA, FFSc (RCPA)§,∥,¶; Garratt, John RT†,‡,#; Gilks, Blake MD, FRCPC†,‡,**; Hyjek, Elizabeth MD, PhD*; Ibrahim, Merdol PhD††; Miller, Rodney MD‡‡; Nielsen, Søren HT, CT§§,∥∥; Petcu, Eugen B. MD, PhD§; Swanson, Paul E. MD¶¶; Taylor, Clive R. MD, PhD##; Vyberg, Mogens MD§§,∥∥

Applied Immunohistochemistry & Molecular Morphology: April 2014 - Volume 22 - Issue 4 - p 241–252
doi: 10.1097/PAI.0000000000000069
Review Articles

Standardization of controls, both positive and negative controls, is needed for diagnostic immunohistochemistry (dIHC). The use of IHC-negative controls, irrespective of type, although well established, is not standardized. As such, the relevance and applicability of negative controls continues to challenge both pathologists and laboratory budgets. Despite the clear theoretical notion that appropriate controls serve to demonstrate the sensitivity and specificity of the dIHC test, it remains unclear which types of positive and negative controls are applicable and/or useful in day-to-day clinical practice. There is a perceived need to provide “best practice recommendations” for the use of negative controls. This perception is driven not only by logistics and cost issues, but also by increased pressure for accurate IHC testing, especially when IHC is performed for predictive markers, the number of which is rising as personalized medicine continues to develop. Herein, an international ad hoc expert panel reviews classification of negative controls relevant to clinical practice, proposes standard terminology for negative controls, considers the total evidence of IHC specificity that is available to pathologists, and develops a set of recommendations for the use of negative controls in dIHC based on “fit-for-use” principles.

*Laboratory Medicine Program, University Health Network/University of Toronto, Toronto, ON

#Department of Pathology, Lions Gate Hospital

**Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada

Canadian Immunohistochemistry Quality Control

CAP-ACP National Standards Committee for High Complexity Testing/Immunohistochemistry

§Griffith University School of Medicine, Gold Coast

Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Qld, Australia

Convenor Immunohistochemistry, Anatomical Pathology Program, RCPA QAP Pty Ltd.

††University College London, UK NEQAS ICC&ISH, London, UK

‡‡ProPath, Dallas, TX

§§Institute of Pathology, Aalborg University Hospital, Aalborg, Denmark

∥∥Nordic Immunohistochemical Quality Control (NordiQC)

¶¶Department of Pathology, University of Washington, Seattle, WA

##Department of Pathology, Keck School of medicine, University of Southern California, Los Angeles, CA

The authors declare no conflict of interest.

Reprints: Emina E. Torlakovic, MD, PhD, Department of Laboratory Hematology, Toronto General Hospital/UHN, Pathology, 11th Floor, R411, 200 Elizabeth Street, Toronto, ON, Canada M5G 2C4 (e-mail:

Received January 24, 2014

Accepted January 25, 2014

© 2014 Lippincott Williams & Wilkins, Inc.