Interobserver variation in CD 30 immunohistochemistry interpretation; consequences for patient selection for targeted treatment

Aims CD 30 immunohistochemistry ( IHC ) in malignant lymphoma is used for selection of patients in clinical trials using brentuximab vedotin, an antibody drug‐conjugate targeting the CD 30 molecule. For reliable implementation in daily practice and meaningful selection of patients for clinical trials, information on technical variation and interobserver reproducibility of CD 30 immunohistochemistry ( IHC ) staining is required. Methods and results We conducted a three‐round reproducibility assessment of CD 30 scoring for categorised frequency and intensity, including a technical validation, a ‘live polling’ pre‐ and post‐instruction scoring round and a web‐based round including individual scoring with additional IHC information to mimic daily diagnostic practice. Agreement in all three scoring rounds was poor to fair (κ = 0.12–0.35 for CD 30‐positive tumour cell percentage and κ = 0.16–0.41 for staining intensity), even when allowing for one category of freedom in percentage of tumour cell positivity (κ = 0.30–0.61). The first round with CD 30 staining performed in five independent laboratories showed objective differences in staining intensity. In the second round, approximately half the pathologists changed their opinion on CD 30 frequency after a discussion on potential pitfalls, highlighting hesitancy in decision‐making. Using fictional cut‐off points for percentage of tumour cell positivity, agreement was still suboptimal (κ = 0.35–0.60). Conclusions Lack of agreement in cases with heterogeneous expression is shown to influence patient eligibility for treatment with brentuximab vedotin, both in clinical practice and within the context of clinical trials, and limits the potential predictive value of the relative frequency of CD 30‐positive neoplastic cells for clinical response.