Significant inter‐ and intra‐laboratory variation in grading of invasive breast cancer: A nationwide study of 33,043 patients in the Netherlands

Abstract

Accurate, consistent and reproducible grading by pathologists is of key‐importance for identification of individual patients with invasive breast cancer (IBC) that will or will not benefit from adjuvant systemic treatment. We studied the laboratory‐specific grading variation using nationwide real‐life data to create insight and awareness in grading variation. Synoptic pathology reports of all IBC resection‐specimens, obtained between 2013 and 2016, were retrieved from the nationwide Dutch Pathology Registry (PALGA). Absolute differences in laboratory‐proportions of Grades I–III were compared to the national reference. Multivariable logistic regression provided laboratory‐specific odds ratios (ORs) for high‐ vs. low‐grade IBC. 33,792 IBC pathology reports of 33,043 patients from 39 laboratories were included, of which 28.1% were reported as Grade I (range between laboratories 16.3–43.3%), 47.6% as Grade II (38.4–57.8%), and 24.3% as Grade III (15.5–34.3%). Based on national guidelines, the indication for adjuvant chemotherapy was dependent on histologic grade in 29.9% of patients. After case‐mix correction, 20 laboratories (51.3%) showed a significantly deviant OR. Significant grading differences were also observed among pathologists within laboratories. In this cohort of 33,043 breast cancer patients, we observed substantial inter‐ and intra‐laboratory variation in histologic grading. It can be anticipated that this has influenced outcome including exposure to unnecessary toxicity, since choice of adjuvant chemotherapy was dependent on grade in nearly a third of patients. Better standardization and training seems warranted.

Variability in Breast Cancer Biomarker Assessment and the Effect on Oncological Treatment Decisions: A Nationwide 5-Year Population-Based Study

“…We demonstrated that there was limited variability in ER, PR, and HER2 positivity rates among pathology departments. Overall positivity rates were 87.9% for ER, 72.8% for PR, and 13.1% for HER2, with a median Ki67 proliferation index of 22% and 51.4% of tumors deemed grade II, which are in line with international findings [ 19 , 20 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. Although the proportion HER2 positivity ranged from 9.4% to 16.3% (thus varying from 1 positive out of 6 tested patients to 1 positive out of 11 patients tested), the confidence intervals were broadly overlapping for the vast majority of the labs.…”

“…On the other hand, we also demonstrated unacceptable inter- and intra-laboratory variability in histological grade and Ki67 assessment, urging imminent efforts to further standardize testing procedures. In a large study of 33,043 non-selected breast cancer patients, van Dooijeweert et al also demonstrated a substantial variability in histological grading among pathology departments [ 29 ]. It has long been acknowledged that both Ki67 and histological grade provide useful prognostic information [ 30 , 33 , 34 ].…”

Assessment of tumour proliferation by use of the mitotic activity index, and Ki67 and phosphohistone H3 expression, in early‐stage luminal breast cancer

“…A substantial proportion (30–60%) of patients are diagnosed with grade 2 tumours, and in these patients the indication for adjuvant systemic treatment is less clear. Especially in this category of patients, high interobserver grading variability and institutional inconsistencies have been reported 7–9 …”

Potential of modern circulating cell-free DNA diagnostic tools for detection of specific tumour cells in clinical practice

“…There is a connection between the degree of breast cancer and the mutation that caused it ( 40 ). However, enormous differences were found between inter- and intra-laboratory interpretations of the classification of breast cancer ( 41 ).…”