Virchows Archiv

, Volume 464, Issue 5, pp 539–545 | Cite as

Interpretation of HER2 tests in gastric cancer: confirmation of interobserver differences and validation of a QA/QC educational program

  • Ryoji Kushima
  • Takeshi Kuwata
  • Takashi Yao
  • Hiroshi Kuriki
  • Kaoru Hashizume
  • Shinobu Masuda
  • Hitoshi Tsuda
  • Atsushi Ochiai
Original Article


Accurate testing for human epidermal growth factor 2 (HER2)-positive status is now mandatory to identify gastric cancer patients that will respond to trastuzumab treatment. Immunohistochemistry testing is the primary method used in hospitals. We performed a study of diagnostic accuracy by assessing interobserver variability in immunohistochemistry scoring of HER2 and determined the effectiveness of an educational program for general pathologists that used full sections of gastric cancer specimens. A first ring study (Japanese gastric cancer [JGC] ring study) was performed by five expert pathologists, using 50 whole surgical sections selected by a coordinator, to confirm interobserver discrepancies. A second study (quality assurance/quality control program) involved administration of an educational program to 49 general pathologists that consisted of (i) comments and explanation for a set of pre-educational program cases, (ii) a lecture, and (iii) presentation of typical and special cases for discussion. Effectiveness was measured by comparing indices of the difference between scores before and after the program. The JGC ring study demonstrated good agreement in the interpretation of HER2-immunohistochemistry. Kappa coefficients among the five observers were 0.73 (substantial) and 0.84 (almost perfect) in 4 × 4 and 3 × 3 cross tests, respectively. In the second study, the concordance rate and kappa coefficients improved from pre-educational program levels of 78.6 % and 0.68, respectively, to post-educational program levels of 87.1 % and 0.79, respectively. The present results suggest that effective educational programs reduce interobserver differences between pathologists and provide optimal information regarding patient selection for treatment.


HER2 Immunohistochemistry Gastric carcinoma Ring study Educational quality assurance/quality control program 



We thank all the pathologists who participated and cooperated in this educational program. The authors would also like to thank Dr Ludovic Croxford for providing medical writing support. This study and the medical writing support were supported by Chugai Pharmaceutical Co., Ltd. Tokyo, Japan.

Conflict of interest

RK, TK, TY, SM, HT, and AO have received honoraria for attendance at pathological advisory boards and consensus meetings from Chugai Pharmaceutical Co., Ltd. Tokyo, Japan. HK and KH are full-time employees of Chugai Pharmaceutical Co., Ltd. Tokyo, Japan.


  1. 1.
    Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182PubMedCrossRefGoogle Scholar
  2. 2.
    Fukushige S, Matsubara K, Yoshida M, Sasaki M, Suzuki T, Semba K, Toyoshima K, Yamamoto T (1986) Localization of a novel v-erbB-related gene, c-erbB-2, on human chromosome 17 and its amplification in a gastric cancer cell line. Mol Cell Biol 6:955–958PubMedCentralPubMedGoogle Scholar
  3. 3.
    Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792PubMedCrossRefGoogle Scholar
  4. 4.
    Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659–1672PubMedCrossRefGoogle Scholar
  5. 5.
    Gianni L, Eiermann W, Semiglazov V et al (2010) Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 375:377–384PubMedCrossRefGoogle Scholar
  6. 6.
    Bang YJ, Van Cutsem E, Feyereislova A et al (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376:687–697PubMedCrossRefGoogle Scholar
  7. 7.
    Rüschoff J, Hanna W, Bilous M, Hofmann M, Osamura RY, Penault-Llorca F, van de Vijver M, Viale G (2012) HER2 testing in gastric cancer: a practical approach. Mod Pathol 25:637–650PubMedCrossRefGoogle Scholar
  8. 8.
    Cohen J (1960) A coefficient of agreement for nominal scales. Educ Psychol Meas 20:37–46CrossRefGoogle Scholar
  9. 9.
    Landis JR, Koch GG (1977) The measurement of observer agreement for categorical data. Biometrics 33:159–174PubMedCrossRefGoogle Scholar
  10. 10.
    Dowsett M, Barlett J, Ellis IO et al (2003) Correlation between immunohistochemistry (HercepTest) and fluorescence in situ hybridization (FISH) for HER-2 in 426 breast carcinomas from 37 centres. J Pathol 199:418–423PubMedCrossRefGoogle Scholar
  11. 11.
    Dowsett M, Hanna WM, Kockx M, Penault-Llorca F, Rüschoff J, Gutjahr T, Habben K, van de Vijver MJ (2007) Standardization of HER2 testing: results of an international proficiency-testing ring study. Mod Pathol 20:584–591PubMedCrossRefGoogle Scholar
  12. 12.
    Umemura S, Osamura RY, Akiyama F et al (2008) What cause discrepancies in HER2 testing in breast cancer? Japanese ring study in conjunction with the global standard. Am J Clin Pathol 130:883–891PubMedCrossRefGoogle Scholar
  13. 13.
    Rüschoff J, Dietel M, Baretton G et al (2010) HER2 diagnostics in gastric cancer-guideline validation and development of standardized immunohistochemical testing. Virchows Arch 457:299–307PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Kim KC, Koh YW, Chang HM, Kim TH, Yook JH, Kim BS, Jang SJ, Park YS (2011) Evaluation of HER2 protein expression in gastric carcinomas: comparative analysis of 1,414 cases of whole-tissue sections and 595 cases of tissue microarrays. Ann Surg Oncol 18:2833–2840PubMedCrossRefGoogle Scholar
  15. 15.
    Fox SB, Kumarasinghe MP, Armes JE et al (2012) Gastric HER2 testing study (GaTHER): an evaluation of gastric/gastroesophageal junction cancer testing accuracy in Australia. Am J Surg Pathol 36:577–582PubMedCrossRefGoogle Scholar
  16. 16.
    Hofmann M, Stoss O, Shi D et al (2008) Assessment of a HER2 scoring system for gastric cancer; results from a validation study. Histopathology 52:797–805PubMedCrossRefGoogle Scholar
  17. 17.
    Lee HE, Park KU, Yoo SB, Nam SK, Park DJ, Kim HH, Lee HS (2013) Clinical significance of intratumoral HER2 heterogeneity in gastric cancer. Eur J Cancer 49:1448–1457PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Ryoji Kushima
    • 1
    • 9
  • Takeshi Kuwata
    • 2
  • Takashi Yao
    • 3
  • Hiroshi Kuriki
    • 4
  • Kaoru Hashizume
    • 5
  • Shinobu Masuda
    • 6
  • Hitoshi Tsuda
    • 7
  • Atsushi Ochiai
    • 8
  1. 1.Department of Pathology and Clinical LaboratoriesNational Cancer Center HospitalTokyoJapan
  2. 2.Department of Pathology and Clinical LaboratoriesNational Cancer Center Hospital EastKashiwaJapan
  3. 3.Department of Human PathologyJuntendo UniversityTokyoJapan
  4. 4.Clinical Research Planning DepartmentChugai Pharmaceutical Co., Ltd.TokyoJapan
  5. 5.Medical Plan Management DepartmentChugai Pharmaceutical Co., Ltd.TokyoJapan
  6. 6.Department of PathologyNihon University School of MedicineTokyoJapan
  7. 7.Department of Basic PathologyNational Defense Medical CollegeSaitamaJapan
  8. 8.Division of PathologyResearch Center for Innovative Oncology, National Cancer Center Hospital EastKashiwaJapan
  9. 9.Department of Pathology and Clinical LaboratoriesNational Cancer Center HospitalTokyoJapan

Personalised recommendations