Prognostic value of histopathological DCIS features in a large-scale international interrater reliability study

Emma J. Groen, Jan Hudecek, Lennart Mulder, Maartje van Seijen, Mathilde M. Almekinders, Stoyan Alexov, Aniko Kovacs, Ales Ryska, Zsuzsanna Varga, Francisco-Javier Andreu Navarro, Simonetta Bianchi, Willem Vreuls, Eva Balslev, Max Boot, Janina Kulka, Ewa Chmielik, Ellis Barbe, Mathilda J. de Rooij, Winand Vos, Andrea FarkasNatalja E. Leeuwis-Fedorovich, Peter Regitnig, Pieter J. Westenend, Loes F. S. Kooreman, Cecily Quinn, Giuseppe Floris, Gabor Cserni, Paul J. van Diest, Esther H. Lips, Michael Schaapveld, Jelle Wesseling*, Grand Challenge PRECISION consortium

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Purpose For optimal management of ductal carcinoma in situ (DCIS), reproducible histopathological assessment is essential to distinguish low-risk from high-risk DCIS. Therefore, we analyzed interrater reliability of histopathological DCIS features and assessed their associations with subsequent ipsilateral invasive breast cancer (iIBC) risk. Methods Using a case-cohort design, reliability was assessed in a population-based, nationwide cohort of 2767 women with screen-detected DCIS diagnosed between 1993 and 2004, treated by breast-conserving surgery with/without radiotherapy (BCS +/- RT) using Krippendorff's alpha (KA) and Gwet's AC2 (GAC2). Thirty-eight raters scored histopathological DCIS features including grade (2-tiered and 3-tiered), growth pattern, mitotic activity, periductal fibrosis, and lymphocytic infiltrate in 342 women. Using majority opinion-based scores for each feature, their association with subsequent iIBC risk was assessed using Cox regression. Results Interrater reliability of grade using various classifications was fair to moderate, and only substantial for grade 1 versus 2 + 3 when using GAC2 (0.78). Reliability for growth pattern (KA 0.44, GAC2 0.78), calcifications (KA 0.49, GAC2 0.70) and necrosis (KA 0.47, GAC2 0.70) was moderate using KA and substantial using GAC2; for (type of) periductal fibrosis and lymphocytic infiltrate fair to moderate estimates were found and for mitotic activity reliability was substantial using GAC2 (0.70). Only in patients treated with BCS-RT, high mitotic activity was associated with a higher iIBC risk in univariable analysis (Hazard Ratio (HR) 2.53, 95% Confidence Interval (95% CI) 1.05-6.11); grade 3 versus 1 + 2 (HR 2.64, 95% CI 1.35-5.14) and a cribriform/solid versus flat epithelial atypia/clinging/(micro)papillary growth pattern (HR 3.70, 95% CI 1.34-10.23) were independently associated with a higher iIBC risk. Conclusions Using majority opinion-based scores, DCIS grade, growth pattern, and mitotic activity are associated with iIBC risk in patients treated with BCS-RT, but interrater variability is substantial. Semi-quantitative grading, incorporating and separately evaluating nuclear pleomorphism, growth pattern, and mitotic activity, may improve the reliability and prognostic value of these features.

Original languageEnglish
Pages (from-to)759-770
Number of pages12
JournalBreast Cancer Research and Treatment
Issue number3
Publication statusPublished - Oct 2020


  • Ductal carcinoma in situ
  • Invasive breast cancer
  • Interrater reliability
  • Risk stratification
  • RISK


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