Abstract
PurposeFor 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.MethodsUsing 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.ResultsInterrater 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.ConclusionsUsing 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.
Highlights
Ductal carcinoma in situ (DCIS) of the breast is a non-obligate precursor of invasive breast cancer (IBC)
DCIS Ductal carcinoma in situ IBC Invasive breast cancer ipsilateral IBC (iIBC) Ipsilateral invasive breast cancer 95% CI 95% Confidence Interval BCS ± RT Breast-conserving surgery with or without radiotherapy NCR Netherlands Cancer Registry
We subsequently evaluate whether these features, based on a more robust majority opinion of 38 raters, are associated with risk of development of subsequent iIBC
Summary
Ductal carcinoma in situ (DCIS) of the breast is a non-obligate precursor of invasive breast cancer (IBC). Since the introduction of organized population-based breast screening, the incidence of DCIS has increased manyfold [1,2,3]. DCIS is almost always treated to avoid progression to IBC, this has not led to a reduced IBC incidence. It has been reported that a large proportion of untreated DCIS will not progress to IBC [7, 8]. Ryser et al reported a 10-year net risk of ipsilateral IBC (iIBC) of 12.2% (95% Confidence Interval (95% CI) 8.6–17.1%) for women with DCIS grade 1/2 and 17.6% (95% CI 12.1–25.2%) for grade 3 [8]. Based on selected patients, these results underline that at least some DCIS lesions have a low risk of progression and may be overtreated. Reliably distinguishing high- from low-risk DCIS to guide treatment is still challenging
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