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

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.

Variability in grading of ductal carcinoma in situ among an international group of pathologists

“…It is therefore difficult to know if the greater concordance of the three UK pathologists represents the recent focus on consistency of grading of DCIS in the UK; the overall educational and quality assurance mechanisms in place; or simply that they have had the opportunity to work together, discuss problematic cases, and align their approach to DCIS grading. Nevertheless, this supports the use of one international DCIS grading system along with a uniform training programme, as also suggested by other studies [1,[18][19][20]28].…”

“…The proportion of pure DCIS that is ER positive is 68-83% [5,[29][30][31][32], while HER2 positivity ranges from 25 to 35% [5,30,31,33]. IHC scoring for ER and HER2 is reported to have high interobserver agreement between pathologists (intraclass coefficient > 0.8) [5], which is better than the interobserver agreement for grade (presented here and in other studies [18][19][20][21][34][35][36]). Globally, the use of IHC within DCIS is variable; no marker is currently included in the international DCIS pathology minimum data sets, although in some national data sets (e.g.…”

“…This discrepancy might result in a low correlation between prognosis and grade. Multiple studies have shown high inter-rater variability of DCIS grade and have suggested methods for improvements in consistency, such as dichotomous scoring [18][19][20], assessing the proportions of DCIS heterogeneity [21], adding uniform e-learning [22], and using second opinions [23]. Our results are based on a GLMM taking into account that the same pathologists examined the same slides [24].…”

Comment on: “Pathological features of 11,337 patients with primary ductal carcinoma in situ (DCIS) and subsequent events: results from the UK Sloane Project”

“…Interestingly, Groen et al showed that the median time to invasive recurrence does not significantly differ between low-grade and high-grade DCIS (5,3 versus 5,6 years), nor between BCS alone versus BCS and radiotherapy (5,1 versus 5,9 years). 8 It is clear from the work by Shaaban et al and others that the risk of in situ recurrence is highest in the first five post-operative years, and thereafter, disease-specific survival curves show a changed slope. We believe that these observations, together with the fact that DCIS patients with invasive recurrence have a significantly worse disease-free and overall survival in both the real-world and randomised trial setting, 3,4,9 are sufficiently strong arguments to demand separate reports on the median time to in situ versus invasive recurrence in all future studies on prognostic markers in DCIS.…”

Low-risk DCIS. What is it? Observe or excise?

“…kappa value of 0.55 in the UK Breast External Quality Assurance Scheme [43], several recent studies have shown that there is variability between pathologists, particularly internationally. [9,44] Indeed, whilst most of the literature demonstrates prognostic value to DCIS grade, not all does, which may reflect inter-observer variability as well as the use of different guidelines for definitions of grades. In one recent multi-centre study from the UK, the USA and the Netherlands, an overall kappa for grade of DCIS (low, intermediate or high) was 0.50 (95% CI 0.44-0.56); the pathologists using one set of pathology guidelines from one country had a mildly higher association (kappa = 0.58; 95% CI 0.56-0.61) but it may be that stricter adherence to guidelines is necessary.…”