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A Systematic Review and Meta-Analysis of the Diagnostic Performance of BRAF V600E Immunohistochemistry in Thyroid Histopathology

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Abstract

Immunohistochemistry (IHC) in evaluating thyroid surgical specimens may facilitate diagnostic and prognostic evaluation, with potential therapeutic implications. We performed a systematic review and meta-analysis examining the analytic validity of IHC in detecting BRAFV600E mutations in thyroid cancer (primary or metastatic). We screened citations from three electronic databases (until December 20, 2018), supplemented by a hand search of authors’ files and cross-references of reviews. Citations and full-text papers were independently reviewed in duplicate, and consensus was achieved on inclusion of papers. Two reviewers independently critically appraised and abstracted data from included papers. Random-effect meta-analyses were conducted for sensitivity and specificity estimates. We reviewed 1499 unique citations and 93 full-text articles. We included 1 systematic review and 30 original articles. The published review (from 2015) needed to be updated as there were multiple subsequent original studies. The pooled sensitivity of IHC in detecting a BRAFV600E mutation was 96.8% (95% confidence interval [CI] at 94.1%, 98.3%) (29 studies, including 2659 BRAFV600E mutant tumors). The IHC pooled specificity was 86.3% (95% CI 80.7%, 90.4%) (28 studies, including 1107 BRAFV600E wild-type specimens). These meta-analyses were subject to statistically significant heterogeneity, partly explained by antibody type (sensitivity and specificity) and tissue/tumor type (specificity). In conclusion, BRAF IHC is highly sensitive and reasonably specific in detecting the BRAFV600E mutation; however, there is some variability in analytic performance.

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Acknowledgments

The authors would like to thank Mrs. Coreen Marino, for assistance in retrieving full-text papers.

Funding

None.

Author information

Authors and Affiliations

  1. Thyroid Fellow, University of Toronto, Toronto, Canada

    Ranjit Singarayer

  2. Toronto General Hospital, 200 Elizabeth Street, 12 EN-212, Toronto, Ontario, M5G 2C, Canada

    Ranjit Singarayer

  3. Department of Pathology, University Health Network and University of Toronto, Toronto, Canada

    Ozgur Mete & Sylvia L. Asa

  4. Toronto General Hospital, 200 Elizabeth Street, 11 EN-422, Toronto, Ontario, M5G 2C4, Canada

    Ozgur Mete & Sylvia L. Asa

  5. University of Toronto Libraries, University of Toronto, 130 St. George St, Toronto, Ontario, Canada

    Laure Perrier

  6. Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada

    Lehana Thabane

  7. St. Joseph’s Healthcare Hamilton, Biostatistics Unit, 3rd Floor, Martha Wing, Room H-325, 50 Charlton Avenue East, Hamilton, Ontario, L8N 4A6, Canada

    Lehana Thabane

  8. Division of Endocrinology, Western University, London, Ontario, Canada

    Stan Van Uum

  9. Division of Endocrinology & Metabolism, St Joseph’s Health Care London, Room B5-130, 268 Grosvenor Street, London, Ontario, Canada

    Stan Van Uum

  10. Department of Endocrine Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada

    Shereen Ezzat

  11. Toronto General Hospital, 585 University Avenue, 9NU-986, Toronto, Ontario, M5G 2N2, Canada

    Shereen Ezzat

  12. Department of Otolaryngology, Head and Neck Surgery, University Health Network and University of Toronto, Toronto, Canada

    David P. Goldstein

  13. Princess Margaret Cancer Centre, 610 University Avenue, Suite 3-950, Toronto, Ontario, M5G 2M9, Canada

    David P. Goldstein

  14. Division of Endocrinology, University Health Network and University of Toronto, Toronto, Canada

    Anna M. Sawka

  15. Toronto General Hospital, 200 Elizabeth Street, 12 EN-212, Toronto, Ontario, M5G 2C4, Canada

    Anna M. Sawka

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  1. Ranjit Singarayer
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Appendices

Appendix 1 Sample Search Strategy

Database: Ovid MEDLINE: Epub ahead of print, in-process, and other non-indexed citations, Ovid MEDLINE® Daily and Ovid MEDLINE® <1946–Present>

  1. 1

    1 exp thyroid neoplasms/

  2. 2

    (thyroid adj cancer$).mp.

  3. 3

    (thyroid adj carcinoma$).mp.

  4. 4

    (thyroid adj neoplasm$).mp.

  5. 5

    (thyroid adj adenoma$).mp.

  6. 6

    (thyroid adj tumo?r$).mp.

  7. 7

    or/1–6

  8. 8

    BRAF$.mp.

  9. 9

    B-raf$.mp.

  10. 10

    “proto-oncogene B-Raf”.mp.

  11. 11

    NS7.mp.

  12. 12

    “p94”.mp.

  13. 13

    “proto-oncogene B-Raf”.mp.

  14. 14

    “murine sarcoma viral (v-raf) oncogene homolog B1”.mp.

  15. 15

    RAFB1.mp.

  16. 16

    “94 kDa B-raf protein”.mp.

  17. 17

    “v-raf murine sarcoma viral oncogene homolog B”.mp.

  18. 18

    “v-raf murine sarcoma viral oncogene homolog B1”.mp.

  19. 19

    or/8–18

  20. 20

    exp. Immunohistochemistry/

  21. 21

    Histocytochemistry/

  22. 22

    Biomarkers, Tumor/

  23. 23

    “Staining and Labeling”/

  24. 24

    immunohistochem$.mp.

  25. 25

    histocytochem$.mp.

  26. 26

    immunocytochem$.mp.

  27. 27

    immunohistocytochem$.mp.

  28. 28

    immunostain$.mp.

  29. 29

    biomarker$.mp.

  30. 30

    histochem$.mp.

  31. 31

    marker$.mp.

  32. 32

    stain$.mp.

  33. 33

    (mark$ adj3 agent$).mp.

  34. 34

    (antibod$ adj3 label$).mp.

  35. 35

    (immun$ adj3 label$).mp.

  36. 36

    immunolabel$.mp.

  37. 37

    or/20–36

  38. 38

    7 and 19 and 37

  39. 39

    exp. animals/not (exp animals/and humans/)

  40. 40

    38 not 39

  41. 41

    limit 40 to yr=“2005–Current”

Appendix 2

Table 5 Details of the full-text papers that were reviewed and excluded (with reasons for exclusion)
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Singarayer, R., Mete, O., Perrier, L. et al. A Systematic Review and Meta-Analysis of the Diagnostic Performance of BRAF V600E Immunohistochemistry in Thyroid Histopathology. Endocr Pathol 30, 201–218 (2019). https://doi.org/10.1007/s12022-019-09585-2

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