TY - JOUR
T1 - Prognostic value of histopathological DCIS features in a large-scale international interrater reliability study
AU - Groen, Emma J.
AU - Hudecek, Jan
AU - Mulder, Lennart
AU - van Seijen, Maartje
AU - Almekinders, Mathilde M.
AU - Alexov, Stoyan
AU - Kovacs, Aniko
AU - Ryska, Ales
AU - Varga, Zsuzsanna
AU - Navarro, Francisco-Javier Andreu
AU - Bianchi, Simonetta
AU - Vreuls, Willem
AU - Balslev, Eva
AU - Boot, Max
AU - Kulka, Janina
AU - Chmielik, Ewa
AU - Barbe, Ellis
AU - de Rooij, Mathilda J.
AU - Vos, Winand
AU - Farkas, Andrea
AU - Leeuwis-Fedorovich, Natalja E.
AU - Regitnig, Peter
AU - Westenend, Pieter J.
AU - Kooreman, Loes F. S.
AU - Quinn, Cecily
AU - Floris, Giuseppe
AU - Cserni, Gabor
AU - van Diest, Paul J.
AU - Lips, Esther H.
AU - Schaapveld, Michael
AU - Wesseling, Jelle
AU - Grand Challenge PRECISION consortium
N1 - Funding Information:
This work was supported by KWF Kankerbestrijding (Grant Number NKI2014-7167) and by Cancer Research UK and by KWF Kankerbestrijding in a joint grant (Grant Number C38317/A24043). Acknowledgements
Funding Information:
The authors thank all collaborating hospitals and PALGA, the nationwide network and registry of histo- and cytopathology, for facilitating retrieval of archival tissue material and providing pathology data. The authors thank the Netherlands Comprehensive Cancer Organization for providing data of the Netherlands Cancer Registry. The authors would like to thank the Dutch screening organization for providing screening data. The authors would like to acknowledge the NKI- AVL Core Facility Molecular Pathology & Biobanking (CFMPB) for supplying lab support. We thank all other pathologists who participated in the study: Mari?tte Giessen, Erik Nijhuis, Erwin Geuken, Frank Bellot, Karen Koopman, Ivana Verlinden, Mari?l Brinkhuis, Franka van Merri?nboer, Gesina van Lijnschoten, Horst B?rger, Alicia C?rdoba, Inta Liepniece-Karele, and Grace Callagy.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/10
Y1 - 2020/10
N2 - 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.
AB - 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.
KW - Ductal carcinoma in situ
KW - Invasive breast cancer
KW - Interrater reliability
KW - Risk stratification
KW - CARCINOMA-IN-SITU
KW - INVASIVE BREAST-CANCER
KW - LOCAL RECURRENCE
KW - PHASE-III
KW - REPRODUCIBILITY
KW - CLASSIFICATION
KW - RISK
KW - PATHOLOGISTS
KW - PROLIFERATION
KW - AGREEMENT
U2 - 10.1007/s10549-020-05816-x
DO - 10.1007/s10549-020-05816-x
M3 - Article
C2 - 32734520
SN - 0167-6806
VL - 183
SP - 759
EP - 770
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 3
ER -