HER2 immunohistochemistry in endometrial and ovarian clear cell carcinoma: discordance between antibodies and with in‐situ hybridisation

Aims Treatment with anti‐ HER 2 therapy could be beneficial for patients with HER 2‐positive endometrial and ovarian clear cell carcinoma ( CCC ). We studied HER 2 overexpression by immunohistochemistry ( IHC ) using three different antibodies, including concordance with amplification by in‐situ hybridisation ( ISH ). Methods and results IHC and ISH were performed on tissue microarrays of 101 tumours: 58 endometrial pure CCC , 19 endometrial mixed carcinomas with a CCC component and 24 ovarian pure CCC . IHC was performed using SP 3, 4B5 and HercepTest antibodies, and was scored by two independent observers. ISH was performed using dual‐colour silver ISH . Using IHC , agreement was poor between SP 3/4B5 (61.4%), poor between SP 3/HercepTest (68.3%) and reasonable between 4B5/HercepTest (75.2%). Interobserver agreement was substantial to almost perfect for all antibodies ( SP 3: linear weighted κ = 0.89, 4B5: κ = 0.90, HercepTest: κ = 0.76). HER 2‐positivity by ISH was 17.8% (endometrial pure CCC : 24.1%, endometrial mixed: 0%, ovarian pure CCC : 16.7%). IHC / ISH concordance was poor, with a high false‐negative rate of all three IHC antibodies: sensitivity (38.9–50.0%) and positive predictive value ( PPV ) (37.5–58.3%) were poor; specificity (81.9–94.0%) and negative predictive value ( NPV ) (87.1–88.3%) were reasonable. When excluding 2+ cases, sensitivity declined (26.7–43.8%) but PPV (80.0–87.5%) and specificity (98.6–98.7%) improved. Conclusions In ovarian and endometrial CCC , there is considerable difference in HER 2 overexpression by different IHC antibodies and marked discordance with ISH . As such, no single antibody can be considered conclusive for determining HER 2 status in CCC . Based on these results, the lack of predictive value of different HER 2 testing methods, as used in other studies, could be explained.