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Original Article

In-depth Retrospective Review of Originally Negative Screening Mammograms from Women with Confirmed Breast Cancer

Authors:

Lieve Vandendaele ,

Universiteit Gent & CvKO, Centrum voor Kankeropsporing, BE
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Svetlana Jidkova,

Universiteit Gent & CvKO, Centrum voor Kankeropsporing, Data Science Institute UZ Gent, BE
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Koen Van Herck,

Universiteit Gent, BE; Belgian Cancer Registry, BE
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Tom Kimpe,

Barco, BE
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Veerle Verschuere

Universiteit Gent & CvKO, Centrum voor Kankeropsporing, BE
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Abstract

Objectives: We aim to contribute to the assessment of the screening performance in Flanders (Belgium) and to identify valuable mammograms for subsequent studies and training.

Materials and Methods: Initially negative prior screening mammograms (sMx) of 210 women with confirmed breast cancer detected by the Flemish screening programme between 2011–2013 were reviewed by a highly experienced radiologist. The review of the prior sMx was performed in three steps: 1) only prior mammograms available; 2) with index sMx (=subsequent positive sMx) present; 3) with index sMx and clinical information present.

Results: The radiological review yielded 94 (45%) mammograms ‘without suspicious lesions’, 77 (37%) ‘with minimal signs in at least one breast’, and 39 (19%) ‘with clearly visible tumours’. In univariate analyses, the reclassification of prior sMx was significantly associated with the date of the prior sMx, the need for a third reader for arbitration, image quality and the detector system used (computed radiography versus direct readout digital radiography), and it was not associated with the interval between screening rounds, age at prior sMx, breast density, or tumour characteristics (<T2 versus ≥T2, in situ versus invasive). In multivariate analyses, the date of the prior sMx (p = 0.001), need for arbitration (p = 0.001) and image quality (p < 0.001) remained significantly associated with the reclassification.

Conclusion: This retrospective review reclassified 19% of the sMx as clearly visible tumours. With this, the Flemish screening programme performs in accordance with similar studies. The sMx reviewed in this study, form a valuable set of mammograms for training and further research.

How to Cite: Vandendaele L, Jidkova S, Van Herck K, Kimpe T, Verschuere V. In-depth Retrospective Review of Originally Negative Screening Mammograms from Women with Confirmed Breast Cancer. Journal of the Belgian Society of Radiology. 2022;106(1):108. DOI: http://doi.org/10.5334/jbsr.2796
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  Published on 11 Nov 2022
 Accepted on 12 Sep 2022            Submitted on 03 Mar 2022

Introduction

Breast cancer screening programmes have substantially increased the number of early detected cancers [1]. However, studies have made clear that current screening programmes only capture about 70% of all breast cancers that occur in participating women [2, 3, 4].

To improve cancer detection by mammography screening the European guidelines advise quality control using predefined performance indicators and quality assurance including review and training. An important performance indicator is rating interval cancers (breast cancers arising after a negative screening episode and before the next scheduled screening round). Performing a radiological review of prior screening mammograms (sMx) of interval cancers is part of the quality assurance and also an important teaching tool [1]. Screen-detected cancers have different characteristics than interval cancers [3, 5], and it is therefore useful to also review the priors of screen-detected cancers in order to improve the programme’s quality [1, 6].

This study comprises a review of confirmed breast cancer cases detected by the Flemish screening programme. The aims were to quantify the proportion of visible tumours on the prior sMx and to gather insight into associated variables that may hinder cancer detection, such as breast density, age, image quality, imaging technique, tumour size, type of tumour, need of arbitration, screening interval, and date of prior sMx. The study also aimed to identify a valuable set of sMx for training and subsequent studies.

Materials and Methods

In the breast cancer screening programme in Flanders, biennial two-view mammographic screening is offered free of charge to women aged 50–69 years. Two radiologists (first and second reader) independently evaluate the screening mammograms, with third reader arbitration if needed.

Between 2009–2013, 254,350 women participated in the Flemish Breast Cancer Screening Programme. From this group, cases for review were selected based on the following inclusion criteria: 1) informed consent for use of data in scientific research, 2) participation in minimum two consecutive screening rounds, 3) a screening interval of 16–30 months, 4) the index sMx (latest sMx) in 2011, 2012, or 2013 resulted in a referral for further diagnostic workup confirming and correctly documenting breast cancer, 5) where the prior sMx (previous sMx) was considered negative, 6) where the index and prior sMx were digital and available in the PACS (Picture Archiving and Communication System) at the Centre for Prevention and Early Detection of Cancer. In total, 292 cases met these inclusion criteria. From those a predefined sample size of 210 was selected by standard SPSS algorithms for random selection.

The 210 prior sMx were thoroughly reviewed by a single, highly experienced radiologist (reading > 10,000 sMx/year since 2006). The review followed a stepwise procedure: 1) review of prior sMx, in the absence of other images or information, 2) review of prior sMx with index sMx (subsequent positive screening mammogram) present, and 3) review of prior sMx, where index sMx and clinical information on tumour localization and characteristics (size, type, and stage) from diagnostic follow up were present. All steps were performed per case in succession. The expert radiologist reviewed all prior sMx for the presence of malignancy, the image quality, and breast density. The reviewing radiologist was not informed of the purpose of the study.

Possible associations between relevant variables and the intermediate (step 2) or final classification (step 3) were studied in univariate (chi-square) and multivariate analyses (logistic regression). 1) Breast density (≤25%, 26–50%, >50%), 2) age (50–54, 55–59, 60–64, 65–69 years), 3) image quality (good/not good), and 4) imaging technique (CR: computed radiography or DR: direct readout digital radiography) were considered as relevant variables with a possible association with non-detection of a visible cancer. Also 5) tumour size (<T2 versus ≥T2), 6) type of tumour (in situ versus invasive), 7) the need of a third reader for arbitration during the original reading process of the prior sMx (arbitration, no arbitration), 8) the interval between prior and index screening (17–20, 21–24, 25–28 months), and 9) the date of screening of prior sMx (earliest, intermediate and latest tertile) were tested. Tertiles were used instead of screening years due to an imbalanced distribution of cases across calendar years (see Table 1).

Table 1

Descriptive analyses of sMx and tumour characteristics.


DESCRIPTIVE DATA N %

Total 210 100

Age at prior sMx1

50–54 years 55 26.2

55–59 years 56 26.7

60–64 years 74 35.2

65–69 years 25 11.9

Date of prior sMx

2009 29 13.8

2010 99 47.1

2011 82 39

Interval between prior and index sMx

17–20 months 19 9

21–24 months 169 80.5

25–28 months 22 10.5

Arbitration needed for prior sMx

No arbitration 189 90

Arbitration 21 10

Digital technique of prior sMx

Computed Radiography (CR) 71 33.8

Direct readout digital Radiography (DR) 139 66.2

Tumour size

<T22 169 80.5

≥T2 37 17.6

Missing 4 1.9

Type of tumour

In situ 29 13.8

Invasive 181 86.2

Staging

Stage 0 (in situ) 26 12.4

Stage IA 95 45.2

Stage IB 13 6.2

Stage IIA 40 19

Stage IIB 12 5.7

Stage IIIA 7 3.3

Stage IIIC 5 2.4

Stage IV 8 3.8

Missing 4 1.9

1 sMx: screening mammogram. 2 T2: Tumour more than 2 cm but not more than 5 cm in greatest dimension.

Because of the limited number of clearly visible tumours in the intermediate and final classification, bootstrap validation with bias correction and accelerated bootstrap interval was performed. Statistical significance was set at p < 0.05.

In the multivariate analysis, the group of clearly visible tumours was first compared with the compound group of minimal and no signs, subsequently the group of clearly visible tumours was compared with the no signs group only.

Results

Descriptive characteristics of sMx

Table 1 lists data from prior and index sMx and diagnostic follow up.

The sMx dataset contained images of 102 left, 103 right, and 5 bilateral breast cancers.

Expert review of prior sMx

The results of the expert review are summarized in Table 2.

Table 2

The results of the expert review of the prior sMx.


STEP 1 REVIEW OF PRIORS ONLY N %

Total 210 100

Image quality of prior sMx1

Good 148 70

Not good technical physical 20 10

Not good positioning 28 13

Not good technical physical nor positioning 14 7

Breast Density on prior sMx

0–25% 80 38.1

26–50% 62 29.5

51–75% 64 30.5

76–100% 4 1.9

Step 1 Bi-RADS categories: Review of prior sMx

No lesion 98 46.7

Benign lesion(s) 41 19.5

Probably benign 47 22.4

Probably malignant 24 11.4

Malignant 0 0

Total 210 100

Step 2 interim classification: Reviewing priors with index sMx available

Without suspicious lesions 97 46.2

Minimal signs 88 41.9

Clearly visible tumour 25 11.9

Total 210 100

Step 3 final classification: Reviewing priors with index sMx and clinical information available

Without suspicious lesions 94 44.8

Minimal signs 77 36.7

Clearly visible tumour 39 18.6

Total 210 100

1 sMx: screening mammogram.

By reviewing prior sMx alone (step 1), 24 of the sMx (11.4%) were labelled ‘probably malignant’ and might have been referred. The intermediate classification (step 2), prior sMx with index sMx present, identified 25 cases (11.9%) with ‘clearly visible tumours’. The final classification of prior sMx (step 3), including the use of index images and clinical information, revealed 39 ‘clearly visible tumours’ (18.6%).

Univariate analyses

The intermediate classification was significantly associated with the date of prior sMx (p =< 0.001) and the need of arbitration on the prior sMx (p = 0.002). The final classification was significantly associated with the date of the prior sMx (p =< 0.001); the need of arbitration (p = 0.004), also with the image quality (p = 0.004) and the detector system used (CR versus DR) (p = 0.036). See Table 3. More ‘clearly visible tumours’ were detected in older sMx, sMx that required arbitration, in sMx of inferior quality, and in those using CR-technique.

Table 3

Univariate analyses: Variables significantly associated with the interim or final classification after reviewing prior mammograms.


A. UNIVARIATE ANALYSES: VARIABLES SIGNIFICANTLY ASSOCIATED WITH THE INTERIM CLASSIFICATION (STEP 2) AFTER REVIEWING PRIORS WITH INDEX IMAGES PRESENT.

VARIABLE & CLASSES WITHOUT SUSPICIOUS LESIONS MINIMAL SIGNS CLEARLY VISIBLE TUMOURS TOTAL PEARSON CHI-SQUARE

97 88 25 210

Need of arbitration on prior imaging 0.002

No arbitration 93 (49%) 78 (41%) 18 (10%) 189

Arbitration 4 (19%) 10 (48%) 7 (33%) 21

Date of prior imaging <0.001

Earliest tertile 32 (67%) 15 (31%) 1 (2%) 48

Intermediate tertile 40 (51%) 31 (39%) 8 (10%) 79

Latest tertile 25 (30%) 42 (51%) 16 (19%) 83

B. UNIVARIATE ANALYSES: VARIABLES SIGNIFICANTLY ASSOCIATED WITH THE FINAL CLASSIFICATION (STEP 3) AFTER REVIEWING PRIORS WITH INDEX IMAGES AND CLINICAL INFORMATION PRESENT.

VARIABLE & CLASSES WITHOUT SUSPICIOUS LESIONS MINIMAL SIGNS CLEARLY VISIBLE TUMOURS TOTAL PEARSON CHI-SQUARE

94 77 39 210

Need of arbitration on prior imaging 0.004

No arbitration 90 (48%) 69 (37%) 30 (16%) 189

Arbitration 4 (19%) 8 (38%) 9 (43%) 21

Date of prior imaging <0.001

Earliest tertile 31 (65%) 15 (31%) 2 (4%) 48

Intermediate tertile 39 (49%) 27 (34%) 13 (17%) 79

Latest tertile 24 (29%) 35 (42%) 24 (29%) 83

Image quality at the tumour side 0.004

Good 76 (43%) 59 (38%) 21 (14%) 156

Not good 18 (33%) 18 (33%) 18 (33%) 54

Detector system used 0.036

Computed Radiography CR 29 (41%) 22 (31%) 20 (28%) 71

Direct Readout Digital Radiography DR 65 (47%) 55 (40%) 19 (14%) 139

Multivariate analyses

When clearly visible tumours were compared to the compound group of minimal and no signs, the need of arbitration on the prior sMx (p = 0.005) and the date of the prior images (p = 0.044) were independently significantly associated with false negative clearly visible tumours in step 2 (i.e., only using prior and index images). When clearly visible tumours were compared only to the group of no signs, the significance level for the need of arbitration (p = 0.001) and date of priors (p = 0.004) appeared even higher.

In step 3, the final classification (i.e., with prior and index images and clinical information available), the need of arbitration (p = 0.001) and the date of the prior images (p = 0.006) were still independently significantly associated with false negative clearly visible tumours. Furthermore, the image quality was statistically significant (p < 0.001). These conclusions held, whether comparing to the compound group of minimal and no signs or only to the no signs group. See Table 4.

Table 4

Multivariate analyses: Variables associated with the interim or final classification after reviewing prior mammograms.


A. MULTIVARIATE ANALYSES: VARIABLES ASSOCIATED WITH THE INTERIM CLASSIFICATION (STEP 2) AFTER REVIEWING PRIORS WITH INDEX IMAGES PRESENT.

VARIABLES & CLASSES CLEARLY VISIBLE TUMOURS COMPARED TO NO OR MINIMAL SIGNS CLEARLY VISIBLE TUMOURS COMPARED TO NO SIGNS

ODDS RATIO 95% CONFIDENCE INTERVAL p-VALUE ODDS RATIO 95% CONFIDENCE INTERVAL p-VALUE

Need of arbitration on prior images 0.005 0.001

No arbitration 1 1

Arbitration 4.85 (1.61–14.61) 0.005 16.65 (2.98–93.00) 0.001

Date of prior imaging 0.044 0.004

Earliest tertile 11.13 (1.39–88.93) 0.024 39.71 (3.43–459.09) 0.003

Intermediate tertile 5.75 (0.68–48.72) 0.109 12.30 (1.06–142.17) 0.045

Latest tertile 1 1

Image quality at the tumour side 0.510 0.220

Good 1 1

Not good 1.40 (0.52–3.78) 0.510 2.02 (0.66–6.20) 0.220

B. MULTIVARIATE ANALYSES: VARIABLES ASSOCIATED WITH THE FINAL CLASSIFICATION (STEP 3) AFTER REVIEWING PRIORS WITH INDEX IMAGES AND CLINICAL INFORMATION PRESENT.

VARIABLE & CLASSES CLEARLY VISIBLE TUMOURS COMPARED TO NO OR MINIMAL SIGNS CLEARLY VISIBLE TUMOURS COMPARED TO NO SIGNS

ODDS RATIO 95% CONFIDENCE INTERVAL p-VALUE ODDS RATIO 95% CONFIDENCE INTERVAL p-VALUE

Need of arbitration on prior images 0.001 0.001

No arbitration 1 1

Arbitration 5.72 (1.99–16.43) 0.001 12.24 (2.80–53.52) 0.001

Date of prior imaging 0.006 0.001

Earliest tertile 11.30 (2.30–55.46) 0.003 29.13 (4.40–193.06) <0.001

Intermediate tertile 5.66 (1.11–28.81) 0.037 10.13 (1.53–67.12) 0.016

Latest tertile 1 1

Image quality at the tumour side <0.001 <0.001

Good 1

Not good 4.41 (1.96–9.34) <0.001

All statistically significant associations were confirmed by bootstrap validation.

Discussion

This review of a substantial set of ‘initially negative’ prior sMx resulted in 39 (19%) being labelled as ‘clearly visible tumours’. This result is in accordance with similar studies [6, 7]. It concerns tumours missed twice during the normal screening procedure (by the first and second reader, or if arbitration was necessary, by the third reader and one of first two readers) and are therefore very valuable for training.

The 19% missed tumours cannot automatically be considered ‘screening errors’, for several reasons:

  1. the proportion of cases with ‘clearly visible tumours’ based on image review alone was 1/3 lower, at 12%. The availability of clinical information is known to alter the reading outcome [8, 9].
  2. Even if we tried to reproduce the conditions of routinely assessing sMx in the screening programme, the radiologist’s attention was presumably triggered by the clustering of challenging image sets, the slightly different protocol form, the specific categorization, and the stepwise assessment for the review [3, 9].
  3. The normal response of the human mind to low probability events (i.e., the low prevalence of cancer in the sMx) can be a substantial contributor to false negative errors in breast cancer screening [4].

Therefore, the clustering of challenging sMx in this study may have affected the reader’s awareness and the results of the review.

The image quality was significantly associated with the final categorisation of clearly visible tumours. This confirms the importance of a good image quality and therefore requires special attention [1].

In order to obtain a sufficient number of prior sMx we had to include sMx from the early stages of digital mammography screening in Flanders. The ‘date of screening’ effect may reflect a learning curve for the radiologists involved in the screening programme.

In several studies, DR detector systems seem to be superior to CR detector systems, also in clinical screening performance. Often higher sensitivity is found with higher cancer detection rates and less interval cancers, especially in dense breasts [2, 10, 11].

Since this review was performed by a single – albeit highly experienced – radiologist, the results of this retrospective review could not be corrected for inter-observer variability. This is a major limitation of this study.

Conclusion

The radiological review yielded 94 (45%) mammograms ‘without suspicious lesions’, 77 (37%) ‘with minimal signs in at least one breast’, and 39 (19%) ‘with clearly visible tumours’. These results are in line with similar studies.

The screening mammograms assessed in this review are valuable for training and subsequent studies.

Data Accessibility Statement

All relevant documentation or data in order to verify the validity of the results presented is available, but not openly. Due to the nature of this research, participants of this study did not agree for their data to be shared publicly.

Abbreviations

sMx: screening mammogram

CR: computed radiography

DR: direct readout digital radiography

PACS: Picture Archiving and Communication System

BI-RADS: Breast Imaging Reporting & Data System

Ethics and Consent

All participants gave their written informed consent for the Breast Cancer screening programme in Flanders, including its quality assessment. This research project was approved by the Ethics Committee of Ghent University hospital (B670201318961).

Acknowledgements

The authors especially would like to acknowledge the dedication of dr Margarete (Griet) Mortier, who performed the expert review reported in this paper. We thank Roos Colman for statistical advice, dr Luc Bleyen and dr Soetkin De Brucker for their assistance in data collection and handling, the Centre for Cancer detection (Centrum voor Kankeropsporing vzw, CvKO) for their cooperation and providing the data for this work.

Funding Information

This study has received funding by the Flemish agency for Innovation and Entrepreneurship (Vlaio) (grant number 130472). Apart from approving this study and providing financial sources Vlaio had no further involvement in this study.

Competing Interests

TK is employee at Barco, Beneluxpark 21, 8500 Kortrijk, Belgium, which part funded the research grant for this project. All other authors have no competing interests.

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