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, Anikó Kovács, Ales Ryska, Zsuzsanna Varga, Francisco Javier Andreu Navarro, Simonetta Bianchi, Willem Vreuls, Eva Balslev, Max V. Boot, Janina Kulka, Ewa Chmielik, Ellis Barbé, Mathilda J. de Rooij, Winand Vos, Andrea FarkasNatalja E. Leeuwis-Fedorovich, Peter Regitnig, Pieter J. Westenend, Loes F.S. Kooreman, Cecily Quinn, Giuseppe Floris, Gábor 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

Abstract

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
JournalBreast Cancer Research and Treatment
DOIs
Publication statusAccepted/In press - 1 Jan 2020

Cite this

Groen, E. J., Hudecek, J., Mulder, L., van Seijen, M., Almekinders, M. M., Alexov, S., ... Grand Challenge PRECISION consortium (Accepted/In press). Prognostic value of histopathological DCIS features in a large-scale international interrater reliability study. Breast Cancer Research and Treatment. https://doi.org/10.1007/s10549-020-05816-x