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.

2nd Department of Pathology Semmelweis University Budapest Hungary

Atryshealth Co S L Barcelona Spain

Department of Clinical Pathology Sahlgrenska University Hospital Gothenburg Sweden

Department of Molecular Pathology Netherlands Cancer Institute Antoni van Leeuwenhoek Amsterdam The Netherlands

Department of Pathology Amsterdam University Medical Center Location VUmc Amsterdam The Netherlands

Department of Pathology and GROW School for Oncology and Developmental Biology Maastricht University Medical Centre Maastricht The Netherlands

Department of Pathology and Laboratory Medicine St Vincent's University Hospital Dublin Ireland

Department of Pathology Bács Kiskun County Teaching Hospital Kecskemét Hungary

Department of Pathology Canisius Wilhelmina Hospital Nijmegen The Netherlands

Department of Pathology Deventer Hospital Deventer The Netherlands

Department of Pathology Gävle Hospital Gävle Sweden

Department of Pathology Herlev University Hospital Herlev Denmark

Department of Pathology Netherlands Cancer Institute Antoni van Leeuwenhoek Plesmanlaan 121 1066 CX Amsterdam The Netherlands

Department of Pathology Oncology Hospital Sofia Bulgaria

Department of Pathology University Hospitals Leuven Leuven Belgium

Department of Pathology University Medical Center Utrecht Utrecht The Netherlands

Department of Pathology University of Szeged Szeged Hungary

Department of Pathology Zuyderland Medical Center Location Sittard Geleen Sittard Geleen The Netherlands

Department of Research IT Netherlands Cancer Institute Antoni van Leeuwenhoek Amsterdam The Netherlands

Diagnostic and Research Institute of Pathology Medical University of Graz Graz Austria

Division of Pathological Anatomy Department of Health Sciences University of Florence Florence Italy

Division of Psychosocial Research and Epidemiology Netherlands Cancer Institute Antoni van Leeuwenhoek Amsterdam The Netherlands

Institute of Pathology and Molecular Pathology University Hospital Zurich Zurich Switzerland

Laboratory for Pathology Dordrecht Dordrecht The Netherlands

Laboratory of Translational Cell and Tissue Research Department of Imaging and Pathology KU Leuven University of Leuven Leuven Belgium

Symbiant Pathology Expert Centre Location ZMC Zaandam The Netherlands

The Fingerland Department of Pathology Charles University Medical Faculty and University Hospital Hradec Kralove Hradec Kralove Czech Republic

Tumor Pathology Department Maria Sklodowska Curie National Research Institute of Oncology Gliwice Branch Gliwice Poland

Zobrazit více v PubMed

Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal carcinoma in Situ of the breast: a systematic review of incidence, treatment, and outcomes. J Natl Cancer Inst. 2010;102(3):170–178. PubMed

Netherlands Comprehensive Cancer Organisation (IKNL). Available from: https://www.cijfersoverkanker.nl

Cancer Research UK. Available from: https://www.cancerresearchuk.org/

Ripping TM, Verbeek ALM, Fracheboud J, De Koning HJ, Van Ravesteyn NT, Broeders MJM. Overdiagnosis by mammographic screening for breast cancer studied in birth cohorts in the Netherlands. Int J Cancer. 2015;137(4):921–929. PubMed

Harding C, Pompei F, Burmistrov D, Welch HG, Abebe R, Wilson R. Breast cancer screening, incidence, and mortality across US counties. JAMA Intern Med. 2015;175(9):1483–1489. PubMed

van Luijt PA, Heijnsdijk EAM, Fracheboud J, Overbeek LIH, Broeders MJM, Wesseling J, et al. The distribution of ductal carcinoma in situ (DCIS) grade in 4232 women and its impact on overdiagnosis in breast cancer screening. Breast Cancer Res. 2016;18(1):47. PubMed PMC

Erbas B, Provenzano E, Armes J, Gertig D. The natural history of ductal carcinoma in situ of the breast: a review. Breast Cancer Res Treat. 2006;97(2):135–144. PubMed

Ryser MD, Weaver DL, Zhao F, Worni M, Grimm LJ, Gulati R, et al. Cancer outcomes in DCIS patients without locoregional treatment. J Natl Cancer Inst. 2019;111(9):952–960. PubMed PMC

Lari SA, Kuerer HM. Biological markers in DCIS and risk of breast recurrence: a systematic review. J Cancer. 2011;2:232. PubMed PMC

Visser LL, Groen EJ, Van Leeuwen FE, Lips EH, Schmidt MK, Wesseling J. Predictors of an invasive breast cancer recurrence after DCIS: A Systematic Review and Meta-analyses. Cancer Epidemiol Biomark Prev. 2019;28(5):835–845. PubMed

Holland R, Peterse JL, Millis RR, Eusebi V, Faverly D, Van de Vijver MJ, et al. Ductal carcinoma in situ: a proposal for a new classification. Semin Diagn Pathol. 1994;11(3):167–180. PubMed

Pinder SE, Duggan C, Ellis IO, Cuzick J, Forbes JF, Bishop H, et al. A new pathological system for grading DCIS with improved prediction of local recurrence: Results from the UKCCCR/ANZ DCIS trial. Br J Cancer. 2010;103(1):94–100. PubMed PMC

Cserni G, Sejben A. Grading Ductal Carcinoma In Situ (DCIS) of the breast – what’s wrong with It? Pathol Oncol Res. 2019;26(2):665–671. doi: 10.1007/s12253-019-00760-8. PubMed DOI PMC

Lagios MD. Duct carcinoma in situ. Pathology and treatment. Surg Clin North Am. 1990;70(4):873–883. PubMed

Silverstein MJ, Poller DN, Waisman JR, Colburn WJ, Barth A, Gierson ED, et al. Prognostic classification of breast ductal carcinoma-in-situ. Lancet. 1995;345(8958):1154–1157. PubMed

Sloane JP, Amendoeira I, Apostolikas N, Bellocq JP, Bianchi S, Boecker W, et al. Consistency achieved by 23 European pathologists in categorizing ductal carcinoma in situ of the breast using five classifications. European Commission Working Group on Breast Screening Pathology. Hum Pathol. 1998;29(10):1056–1062. PubMed

Wells WA, Carney PA, Eliassen MS, Grove MR, Tosteson ANA. Pathologists’ agreement with experts and reproducibility of breast ductal carcinoma-in-situ classification schemes. Am J Surg Pathol. 2000;24(5):651–659. PubMed

Bethwaite P, Smith N, Delahunt B, Kenwright D. Reproducibility of new classification schemes for the pathology of ductal carcinoma in situ of the breast. J Clin Pathol. 1998;51:450–454. PubMed PMC

Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ. WHO classification of tumours of the breast. 4. Lyon: International Agency for Research on Cancer; 2012.

College of American pathologists. Available from: https://documents.cap.org/protocols/cp-breast-dcis-18protocol-4100.pdf

Poller DN, Silverstein MJ, Galea M, Locker AP, Elston CW, Blamey RW, et al. Ideas in pathology. Ductal carcinoma in situ of the breast: a proposal for a new simplified histological classification association between cellular proliferation and c-erbB-2 protein expression. Mod Pathol. 1994;7(2):257–262. PubMed

Elston CW, Sloane JP, Amendoeira I, Apostolikas N, Bellocq JP, Bianchi S, et al. Causes of inconsistency in diagnosing and classifying intraductal proliferations of the breast. Eur J Cancer. 2000;36(14):1769–1772. PubMed

Scott MA, Lagios MD, Axelsson K, Rogers LW, Anderson TJ, Page DL. Ductal carcinoma in situ of the breast: Reproducibility of histological subtype analysis. Hum Pathol. 1997;28(8):967–973. PubMed

Schuh F, Biazús JV, Resetkova E, Benfica CZ, Edelweiss MIA. Reproducibility of three classification systems of ductal carcinoma in situ of the breast using a web-based survey. Pathol Res Pract. 2010;206(10):705–711. PubMed

Schuh F, Biazús JV, Resetkova E, Benfica CZ, Ventura A, de Freitas Uchoa D, et al. Histopathological grading of breast ductal carcinoma in situ: validation of a web-based survey through intra-observer reproducibility analysis. Diagn Pathol. 2015;10(1):93. PubMed PMC

Elmore JG, Longton GM, Carney PA, Geller BM, Onega T, Tosteson ANA, et al. Diagnostic concordance among pathologists interpreting breast biopsy specimens. JAMA. 2015;313(11):1122–1132. PubMed PMC

Verkooijen HM, Peterse JL, Schipper MEI, Buskens E, Hendriks JHCL, Pijnappel RM, et al. Interobserver variability between general and expert pathologists during the histopathological assessment of large-core needle and open biopsies of non-palpable breast lesions. Eur J Cancer. 2003;39(15):2187–2191. PubMed

van Dooijeweert C, van Diest PJ, Willems SM, Kuijpers CCHJ, Overbeek LIH, Deckers IAG. Significant inter- and intra-laboratory variation in grading of ductal carcinoma in situ of the breast: a nationwide study of 4901 patients in the Netherlands. Breast Cancer Res Treat. 2019;174(2):479–488. doi: 10.1007/s10549-018-05082-y. PubMed DOI PMC

Kottner J, Audige L, Brorson S, Donner A, Gajewski BJ, Hroóbjartsson A, et al. Guidelines for Reporting Reliability and Agreement Studies (GRRAS) were proposed. Int J Nurs Stud. 2011;48(6):661–671. PubMed

Elshof LE, Schaapveld M, Schmidt MK, Rutgers EJ, van Leeuwen FE, Wesseling J. Subsequent risk of ipsilateral and contralateral invasive breast cancer after treatment for ductal carcinoma in situ: incidence and the effect of radiotherapy in a population-based cohort of 10,090 women. Breast Cancer Res Treat. 2016;159(3):553–563. PubMed PMC

Casparie M, Tiebosch ATMG, Burger G, Blauwgeers H, Van De Pol A, Van Krieken JHJM, et al. Pathology databanking and biobanking in The Netherlands, a central role for PALGA, the nationwide histopathology and cytopathology data network and archive. Cell Oncol. 2007;29(1):19–24. PubMed PMC

Barlow WE, Ichikawa L, Rosner D, Izumi S. Analysis of case-cohort designs. J Clin Epidemiol. 1999;52(12):1165–1172. PubMed

Hayes AF, Krippendorff K. Answering the call for a standard reliability measure for coding data. Commun Methods Meas. 2007;1(1):77–89.

Gwet KL. Handbook of inter-rater reliability: the definitive guide to measuring the extent of agreement among raters. 4. Gaithersburg: Advanced Analytics, LLC; 2014.

Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33(1):159–174. PubMed

Correa C, McGale P, Taylor C, Davidson N, Gelber R, Piccart M, et al. Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast. J Natl Cancer Inst. 2010;41(41):162–177. PubMed PMC

Donker M, Litière S, Werutsky G, Julien JP, Fentiman IS, Agresti R, et al. Breast-conserving treatment with or without radiotherapy in ductal carcinoma in situ: 15-year recurrence rates and outcome after a recurrence, from the EORTC 10853 randomized phase III trial. J Clin Oncol. 2013;31(32):4054–4059. PubMed

Elshof LE, Tryfonidis K, Slaets L, Van Leeuwen-Stok AE, Skinner VP, Dif N, et al. Feasibility of a prospective, randomised, open-label, international multicentre, phase III, non-inferiority trial to assess the safety of active surveillance for low risk ductal carcinoma in situ: The LORD study. Eur J Cancer. 2015;51(12):1497–1510. PubMed

Francis A, Thomas J, Fallowfield L, Wallis M, Bartlett JMS, Brookes C, et al. Addressing overtreatment of screen detected DCIS. The LORIS trial. Eur J Cancer. 2015;51(16):2296–2303. PubMed

Hwang ES, Hyslop T, Lynch T, Frank E, Pinto D, Basila D, et al. The COMET (Comparison of Operative versus Monitoring and Endocrine Therapy) trial: a phase III randomised controlled clinical trial for low-risk ductal carcinoma in situ (DCIS) BMJ Open. 2019;9(3):e026797. PubMed PMC

Gwet KL. Computing inter-rater reliability and its variance in the presence of high agreement. Br J Math Stat Psychol. 2008;61(1):29–48. PubMed

Bloom HJ, Richardson WW. Histological grading and prognosis in breast cancer a study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer. 1957;11(3):359–377. PubMed PMC

Elston CW, Ellis IO. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991;19(5):403–410. PubMed

Van Bockstal M, Baldewijns M, Colpaert C, Dano H, Floris G, Galant C, et al. Dichotomous histopathological assessment of ductal carcinoma in situ of the breast results in substantial interobserver concordance. Histopathology. 2018;73(6):923–932. PubMed

Dano H, Altinay S, Arnould L, Bletard N, Colpaert C, Dedeurwaerdere F, et al. Interobserver variability in upfront dichotomous histopathological assessment of ductal carcinoma in situ of the breast: the DCISion study. Mod Pathol. 2019;33(3):354–366. PubMed PMC

Visser LL, Elshof LE, Schaapveld M, Van De Vijver K, Groen EJ, Almekinders MM, et al. Clinicopathological risk factors for an invasive breast cancer recurrence after ductal carcinoma in situ-a nested case-control study. Clin Cancer Res. 2018;24(15):3593–3601. PubMed

Kerlikowske K, Molinaro AM, Gauthier ML, Berman HK, Waldman F, Bennington J, et al. Biomarker expression and risk of subsequent tumors after initial ductal carcinoma in situ diagnosis. J Natl Cancer Inst. 2010;102(9):627–637. PubMed PMC

Mohammed ZMA, McMillan DC, Elsberger B, Going JJ, Orange C, Mallon E, et al. Comparison of visual and automated assessment of Ki-67 proliferative activity and their impact on outcome in primary operable invasive ductal breast cancer. Br J Cancer. 2012;106(2):383–388. PubMed PMC

Van Velthuysen MLF, Groen EJ, Sanders J, Prins FA, Van Der Noort V, Korse CM. Reliability of proliferation assessment by Ki-67 expression in neuroendocrine neoplasms: eyeballing or image analysis? Neuroendocrinology. 2014;100(4):288–292. PubMed

Stasik CJ, Davis M, Kimler BF, Fan F, Damjanov I, Thomas P, et al. Grading ductal carcinoma in situ of the breast using an automated proliferation index. Ann Clin Lab Sci. 2011;41(2):122–130. PubMed

Balkenhol MCA, Tellez D, Vreuls W, Clahsen PC, Pinckaers H, Ciompi F, et al. Deep learning assisted mitotic counting for breast cancer. Lab Investig. 2019;99(11):1596–1606. doi: 10.1038/s41374-019-0275-0. PubMed DOI

Bera K, Schalper KA, Rimm DL, Velcheti V, Madabhushi A. Artificial intelligence in digital pathology: new tools for diagnosis and precision oncology. Nat Rev Clin Oncol. 2019;16(11):703–715. doi: 10.1038/s41571-019-0252-y. PubMed DOI PMC

Klimov S, Miligy IM, Gertych A, Jiang Y, Toss MS, Rida P, et al. A whole slide image-based machine learning approach to predict ductal carcinoma in situ (DCIS) recurrence risk. Breast Cancer Res. 2019;21(1):1–19. PubMed PMC

Collins LC, Achacoso N, Haque R, Nekhlyudov L, Fletcher SW, Quesenberry CP, et al. Risk factors for non-invasive and invasive local recurrence in patients with ductal carcinoma in situ. Breast Cancer Res Treat. 2013;139(2):453–460. PubMed PMC