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ARTICLE
Epidemiology
Pathological features of 11,337 patients with primary ductal
carcinoma in situ (DCIS) and subsequent events: results from
the UK Sloane Project
Abeer M. Shaaban
1
, Bridget Hilton
2
, Karen Clements
2
, Elena Provenzano
3,4
, Shan Cheung
2
, Matthew G. Wallis
3,4
, Elinor Sawyer
5
,
Jeremy S. Thomas
6
, Andrew M. Hanby
7
, Sarah E. Pinder
5
, Alastair M. Thompson
8
and on behalf of the Sloane Project
Steering Committee
BACKGROUND: The Sloane audit compares screen-detected ductal carcinoma in situ (DCIS) pathology with subsequent
management and outcomes.
METHODS: This was a national, prospective cohort study of DCIS diagnosed during 2003–2012.
RESULTS: Among 11,337 patients, 7204 (64%) had high-grade DCIS. Over time, the proportion of high-grade disease increased
(from 60 to 65%), low-grade DCIS decreased (from 10 to 6%) and mean size increased (from 21.4 to 24.1 mm). Mastectomy was
more common for high-grade (36%) than for low-grade DCIS (15%). Few (6%) patients treated with breast-conserving surgery (BCS)
had a surgical margin <1 mm. Of the 9191 women diagnosed in England (median follow-up 9.4 years), 7% developed DCIS or
invasive malignancy in the ipsilateral and 5% in the contralateral breast. The commonest ipsilateral event was invasive carcinoma
(n=413), median time 62 months, followed by DCIS (n=225), at median 37 months. Radiotherapy (RT) was most protective
against recurrence for high-grade DCIS (3.2% for high-grade DCIS with RT compared to 6.9% without, compared with 2.3 and 3.0%,
respectively, for low/intermediate-grade DCIS). Ipsilateral DCIS events lessened after 5 years, while the risk of ipsilateral invasive
cancer remained consistent to beyond 10 years.
CONCLUSION: DCIS pathology informs patient management and highlights the need for prolonged follow-up of screen-
detected DCIS.
British Journal of Cancer https://doi.org/10.1038/s41416-020-01152-5
BACKGROUND
Ductal carcinoma in situ (DCIS) is a heterogeneous disease that
has increasingly been diagnosed in the context of mammographic
screening. The natural history, optimal management and follow-
up for DCIS remain controversial.
1
The United Kingdom National
Health Service Breast Screening Programme (NHS BSP) presently
invites women aged 50–70 years to attend for 2 view
mammography every 3 years. The Sloane Project, established in
memory of the breast pathologist Professor John Sloane, is a
prospective cohort study that examines the clinical, radiological
and pathological features, patterns of care and outcomes for
women with non-invasive neoplasia detected within the NHS BSP.
Eighty-two of 94 (87%) UK NHS Breast Screening Units have
submitted data yielding detailed information on one-third of all
DCIS diagnosed via the NHS BSP during the time period.
2
The Sloane Project provides a unique opportunity to explore
unanswered questions regarding screen-detected DCIS. Despite
previous randomised clinical trials
3,4
and large numbers of single-
centre studies on biomarkers,
5–8
the optimal management and
follow-up of patients with DCIS remains controversial. The issue of
over-diagnosis/over-treatment of DCIS has been highlighted and
ongoing clinical trials across the world are attempting to evaluate
active surveillance strategies as an alternative to surgical excision
for low-risk DCIS.
9–12
Large, well-characterised, prospective, multi-
centre series of DCIS represent an invaluable resource providing
real-world information. The consistency of reporting among
www.nature.com/bjc
Received: 26 April 2020 Revised: 28 September 2020 Accepted: 21 October 2020
1
Queen Elizabeth Hospital Birmingham and University of Birmingham, Birmingham, UK;
2
Screening Quality Assurance Service, Public Health England, Birmingham, UK;
3
Addenbrookes Hospital, Cambridge, UK;
4
Cambridge Breast Unit, and NIHR Cambridge Biomedical Research Centre, Cambridge University Hospitals NHS Trust, Cambridge, UK;
5
School of Cancer & Pharmaceutical Sciences, King’s College London and Guy’s and St Thomas’Hospitals NHS Foundation Trust, London, UK;
6
Western General Hospital,
Edinburgh, UK;
7
Leeds Institute of Medical Research at St. James’s, St James’s University Hospital, Leeds, UK and
8
Baylor College of Medicine, Houston, TX, USA
Correspondence: Abeer M. Shaaban (a.shaaban@bham.ac.uk)
These authors jointly supervised this work: Sarah E. Pinder, Alastair M. Thompson.
This work was selected for presentation at the Poster Spotlight Discussion Session, San Antonio Breast Cancer Symposium, Texas, US, December 2019: Shaaban, A. M. et al.
Pathological features and lessons learned from screen detected ductal carcinoma in situ (DCIS) - Results from 11,337 cases in the UK Sloane Project. Cancer Res.80(Suppl),
PD6–PD7 (2020). The work was also presented in an oral communication session at the UK Interdisciplinary Breast Cancer Symposium, Birmingham, UK January 2020. The
presentation was entitled ‘Pathological features and outcome of screen detected ductal carcinoma in situ (DCIS): Updated analysis from the UK Sloane Project’. This abstract has
not been published.
©The Author(s) 2020 Published by Springer Nature on behalf of Cancer Research UK
histopathologists and the distribution of reported parameters,
such as DCIS grade and size, the presence of comedo necrosis and
microinvasion, are relevant for patient management and clinical
trial entry and trends in the reporting of these over time have
largely been unexplored. There is no robust data in the current
literature on the incidence and patterns of atypical lesions
associated with DCIS, the histological identification of which
may also alter patient management. We have therefore analysed,
in detail, the pathological features of a large prospective cohort of
well-characterised screen-detected DCIS patients and associated
atypical epithelial lesions within the Sloane Project, assessed
changes in pathological features over time (2003–2012) and the
development of subsequent ipsilateral, contralateral and distant
metastasis events.
METHODS
Contributing Screening Units completed radiology, pathology,
surgery and radiotherapy proformas prospectively.
13
This included
demographic, diagnostic, treatment and vital status data. A
pathology protocol, based on the UK Royal College of Patholo-
gists/BSP guidelines,
14
advises on the handling and reporting of
specimens to mandatory national standards and contains defini-
tions and guidance for the diagnosis of DCIS, microinvasion as
well as cytonuclear grading, comedo necrosis and the assessment
and reporting of excision margins. Oestrogen receptor, progester-
one receptor and HER2 expression are not routinely evaluated on
DCIS in the UK. Here we present an analysis of the pathological
features of DCIS and of subsequent events, if present, in 11,337
women diagnosed between 2003 and 2012 via breast screening.
Subsequent events, including ipsilateral and contralateral DCIS
and/or invasive disease and distant recurrence that developed
≥6 months following the primary DCIS diagnosis, were collected
up to December 2016.
13
To ensure robustness of information, including patient out-
come, data searching and cross-checking across different data-
bases was conducted to ascertain recurrences. This was performed
by matching patient’s date of birth and NHS number to data
collected from Breast Screening Units and other routinely
collected sources of information, including Hospitals Episode
Statistics, Cancer Waiting Times, the English Cancer Analysis
System, National Cancer Registration and Analysis System and the
English National Radiotherapy data sets.
Statistical analysis
Stata was used for statistical analyses. For continuous variables,
the percentage was calculated as a proportion of the total
number. Some variables, such as size and margin status, were re-
coded into categorical groups for further analysis. Where data
were not normally distributed, Spearman’s rank correlation was
employed. Logistic regression was used to calculate the odds ratio
(OR) for the proportion of cases with high-grade DCIS and the
proportion with microinvasion, with year as a factor and 2003/04
as baseline. Survival was defined as the time between initial DCIS
diagnosis and diagnosis of recurrent breast cancer or metastases.
Patients with no recurrence were censored at date of death/date
last seen. All tests were two sided. A probability value of ≤0.05 was
considered significant.
RESULTS
A summary of the DCIS characteristics of the whole cohort
stratified by treatment type is presented in Table 1.
Size of DCIS
The majority of DCIS lesions submitted to the Sloane Project over
the period 2003–2012 were under 20 mm in extent (n=6067,
54%) although 18% (1989) were >40 mm in size. There was a
statistically significant increase in histological DCIS size, from a
mean of 21.4 mm in 2003–2004 to 24.1 mm in 2011–2012
(Spearman rank correlation test, p< 0.001). This was largely due
to an increase in the proportion of lesions reported as measuring
30 mm or more on histology and particularly an increase in the
proportion of lesions measuring ≥40 mm. As might be expected,
increasing lesion size was associated with a greater likelihood of
patients undergoing mastectomy, with 80% of patients with DCIS
>40 mm treated by mastectomy, compared to 19% of those with
DCIS <40 mm in size.
Grade of DCIS
Of the 11,337 women with primary DCIS, 7204 (64%) had high
cytonuclear grade disease, 27% (3107) were of intermediate grade
and 9% were of low grade; 27 (0.2%) were of unknown grade. Of
note, an increase in the proportion of high-grade DCIS was noted
from 60% of the total in 2004 to 65% in 2012 (60, 61, 62, 64, 62, 67,
64, 67 and 65% in consecutive years), coupled with a decrease in
the proportion of low-grade DCIS, from 10 to 6% from 2003/04 to
2011/12. Logistic regression analysis comparing the years of
diagnosis from 2003/04 to 2011/12 demonstrated that these
trends were statistically significant (p=0.011 for the increase in
the proportion of high-grade DCIS and p=0.001 for the decrease
in the proportion of low-grade DCIS). Breast-conserving surgery
(BCS) was the preferred mode of surgical treatment across all DCIS
grades, but mastectomy was more common in patients with high-
grade DCIS (36%) compared to those with low-grade DCIS (15%)
(Chi
2
170.9, df =1, p< 0.0001).
Architecture of DCIS
Solid DCIS was the predominant architectural pattern, seen in 61%
of cases; 72% of high-grade DCIS was of solid pattern compared
with 49% of intermediate-grade and 21% of low-grade disease.
The second commonest architecture was cribriform (51% of
cases), accounting for 44% of high-grade DCIS and 63 and 68% of
intermediate- and low-grade lesions, respectively. Micropapillary
architecture was seen in 16% of all cases, more commonly of low
or intermediate grade (27 and 18%, respectively) compared to
high-grade DCIS (14%). A papillary architecture was seen in 4% of
DCIS cases, less often of high (3%) than low- or intermediate-grade
disease (7 and 8%, respectively). Flat architecture of DCIS was seen
in 5% of all patients but, intriguingly, was reported in 4% each of
low- and intermediate-grade lesions. Current international guide-
lines classify non-high-grade flat epithelial proliferations as flat
epithelial atypia (FEA) rather than DCIS, although historically it was
categorised as the monomorphic variant of clinging carcinoma, a
term no longer recommended by the World Health Organisation
(WHO) Classification of Tumours Editorial Board.
15
The architectural pattern of DCIS was associated with the
surgical management: patients with flat and micropapillary DCIS
had the highest mastectomy rates (43 and 42%, respectively), with
both these patterns exhibiting larger histological size (31 and 30%
of flat and micropapillary DCIS, respectively measured ≥40 mm).
Comedo necrosis
Comedo necrosis was reported in 61% of cases overall, most
commonly in high-grade DCIS (78%). It was, however, seen in 39%
of intermediate-grade DCIS and 6% of low-grade lesions. The
percentage of DCIS reported as showing comedo necrosis varied
considerably between Units; even excluding centres that con-
tributed <20 DCIS cases, the reported incidence of comedo
necrosis ranged from 22 to 84%.
Margin clearance
Only 3% (233) of patients with BCS had radial margin clearance
described as 0 mm (i.e. involved), with another 3% having disease
<1 mm from the margin. The most common margin width
reported was ≥10 mm (35%, 2814 patients) with 8% (614), 20%
Pathological features of 11,337 patients with primary ductal carcinoma in. . .
AM. Shaaban et al.
2
1234567890();,:
(1559) and 25% (2015) of women undergoing breast conservation
having margin widths of 1–1.9, 2–4.9 and 5–9.9 mm, respectively
(Table 2). In 2%, no margin width was described but the disease
was classified as ‘clear’and in 4% of cases the margin width was
unknown. Thus some 14% of women had margins less than the 2
mm currently considered desirable in the UK and US. Of note,
there was no significant difference in margin width in patients
with DCIS reported to the Sloane Project between 2003 and 2012;
there was no increase in those patients with <1 mm margin or
conversely >5 mm margin widths over this time period.
Microinvasion
Microinvasion was reported as present in 738 women (7%). This
was more frequently seen in association with high-grade DCIS
(8%) but was present in 4% of intermediate-grade and in 1% of
low-grade DCIS. The frequency of microinvasion reported
decreased from 9% in 2003/2004 to 5% in 2011/2012 and logistic
regression confirmed a significant reduction in the presence of
microinvasion by year (comparing 2003/04 to 2011/12; p< 0.001).
Nevertheless, for the overall period, there was very wide variation
in the percentage of microinvasion reported across the submitting
UK pathology departments (range 0–29%).
Associated atypia
Atypical ductal hyperplasia (ADH) was reported in association with
DCIS (with no additional atypia such as lobular neoplasia or FEA)
in 611 patients; this was less frequently seen in association
with high-grade DCIS (3%) than with intermediate-grade (7%) or
Table 1. DCIS characteristics of the whole cohort stratified by treatment groups.
BCS only BCS+RT BCS (RT
unknown)
Mx Total
DCIS grade
Low 693 23.3% 114 2.5% 38 9.5% 151 4.5% 996 8.8%
Intermediate 1371 46.2% 979 21.4% 118 29.6% 633 18.8% 3101 27.4%
High 892 30.0% 3472 76.0% 239 60.1% 2591 76.7% 7194 63.6%
Unknown 13 0.4% 2 0.0% 3 0.8% 1 0.0% 19 0.2%
DCIS architecture
Solid 1356 45.7% 3098 67.8% 240 60.3% 2183 64.7% 6877 60.8%
Cribriform 1709 57.6% 2173 47.6% 182 45.7% 1721 51.0% 5785 51.1%
Micropapillary 474 16.0% 554 12.1% 52 13.1% 774 22.9% 1854 16.4%
Flat 133 4.5% 189 4.1% 20 5.0% 261 7.7% 603 5.3%
Papillary 164 5.5% 168 3.7% 22 5.5% 153 4.5% 507 4.5%
Apocrine 65 2.2% 89 1.9% 3 0.8% 93 2.8% 250 2.2%
Other 23 0.8% 32 0.7% 3 0.8% 34 1.0% 92 0.8%
Unknown 266 9.0% 393 8.6% 46 11.6% 267 7.9% 972 8.6%
Size of DCIS
<10 mm 1553 52.3% 1025 22.4% 103 25.9% 198 5.9% 2879 25.5%
10–20 mm 895 30.1% 1675 36.7% 150 37.7% 466 13.8% 3186 28.2%
20–30 mm 276 9.3% 1078 23.6% 80 20.1% 545 16.1% 1979 17.5%
30–4 mm 91 3.1% 443 9.7% 28 7.0% 509 15.1% 1071 9.5%
>40 mm 59 2.0% 311 6.8% 27 6.8% 1592 47.2% 1989 17.6%
No residual DCIS
a
68 2.3% 19 0.4% 6 1.5% 7 0.2% 100 0.9%
Unknown 27 0.9% 16 0.4% 4 1.0% 59 1.7% 106 0.9%
Comedo necrosis
Present 1097 36.9% 3211 70.3% 215 54.0% 2369 70.2% 6892 60.9%
Absent 1552 52.3% 984 21.5% 105 26.4% 711 21.1% 3352 29.6%
Unknown 320 10.8% 372 8.1% 78 19.6% 296 8.8% 1066 9.4%
Associated epithelial atypia (ADH or lobular neoplasia)
Yes 500 16.8% 448 9.8% 40 10.1% 312 9.2% 1300 11.5%
No 2469 83.2% 4119 90.2% 358 89.9% 3064 90.8% 10,010 88.5%
Microinvasion
Present 82 2.8% 325 7.1% 19 4.8% 313 9.3% 739 6.5%
Absent 2823 95.1% 4178 91.5% 344 86.4% 3018 89.4% 10,363 91.6%
Unknown 64 2.2% 64 1.4% 35 8.8% 45 1.3% 208 1.8%
Margin width
<2 mm 375 13% 644 14% 65 16% 0% 1084 10%
≥2 mm 2410 81% 3719 81% 259 65% 0% 6388 56%
Unknown 184 6% 204 4% 74 19% 0% 462 4%
Total number 2969 100% 4567 100% 398 100% 3376 100% 11,310 100%
a
No residual DCIS in the surgical excision. Lesion was removed by previous core/vacuum-assisted biopsy.
Pathological features of 11,337 patients with primary ductal carcinoma in. . .
AM. Shaaban et al.
3
low-grade disease (14%) (1 unknown) (Table 3). In a further 111
patients, both ADH and lobular in situ neoplasia were present
along with the DCIS, again more commonly in low-grade DCIS
(4%) than in intermediate- (1%) or high-grade disease (<1%)
(Table 3).
Of the women with lobular neoplasia as the only additional
atypical lesion (n=294), 4% was recorded in patients with high-
grade DCIS, 6% with intermediate and 6% in those with low-grade
DCIS (in 3 cases, grade was not known). Pleomorphic lobular
carcinoma in situ was uncommonly reported in the Sloane Project
in patients with DCIS (16 in total); 12 of these women (75%) had
high-grade DCIS (but this represented <1% of all high-grade DCIS
lesions).
Subsequent first events
Subsequent events are defined as the first development of in situ
or invasive breast carcinoma in the ipsilateral or contralateral
breast, or distant metastasis, >6 months following a diagnosis of
DCIS. At the time of writing, up-to-date information was available
for patients from England only (n=9191), and consequently, the
analysis has been limited to English patients and their first episode
of recurrent disease.
Of these 9191 women, 1098 (12%) re-presented with DCIS or
invasive malignancy in the ipsilateral (7%) or contralateral breast
(5%) and 46 (0.5%) patients developed distant recurrence, at a
median of 9.2 years (range 0.4–14.5) follow-up. Ipsilateral invasive
disease (n=413) was more common than ipsilateral DCIS (n=
225). A further 20 patients had an unspecified ipsilateral
recurrence (not known if DCIS or invasive). Contralateral events
were also more commonly invasive (n=325) than in situ (n=94).
Detailed information on three recurrences was not available
(Table 4).
Overall, 377/5753 (6.6%) patients with high-grade DCIS had an
ipsilateral recurrence compared with 210/2550 (8.2%) with
intermediate-grade DCIS and 73/868 (8.4%) with low-grade
disease. When only patients who underwent BCS are considered,
the proportions with any ipsilateral recurrence were more
comparable, amounting to 9.2, 9.7 and 9.8% of high-, inter-
mediate- and low-grade DCIS, respectively. Invasive ipsilateral
recurrence occurred overall after 3.7% of high-grade lesions, 5.7%
of intermediate and 5.6% of those with low-grade DCIS; for
patients undergoing breast conservation, the invasive recurrence
frequencies were 4.9%, 6.7% and 6.7%, respectively.
There was a significant relationship between the grade of
primary DCIS and that of the subsequent DCIS (p< 0.001, Table 5),
whereas there was no statistically significant association between
the grades of DCIS and subsequent invasive disease (p=0.08,
Table 5). Where data were available, subsequent invasive
carcinoma was predominantly of grade 2 in the ipsilateral (46%)
and the contralateral breast (52%), irrespective of the original DCIS
grade. Following a diagnosis of high-grade DCIS, 37% of ipsilateral
or 27% of contralateral invasive carcinomas were grade 3. Low-
grade DCIS was followed by ipsilateral or contralateral invasive
grade 3 carcinoma in 12 and 29% of cases, respectively.
In view of the present UK
16
(and international
17
) guidance
identifying that a 2-mm width of uninvolved tissue is desirable for
DCIS excision, we analysed ipsilateral recurrences (DCIS and
invasive) against margin status (<2 mm or ≥2 mm) following BCS.
Table 3. Associated lesions by DCIS grade.
Associated lesion DCIS grade
High Percent Intermediate Percent Low Percent Unknown All patients
None 6628 92% 2647 85% 752 75% 21 78% 10,048 89%
ADH alone 238 3% 228 7% 144 14% 1 4% 611 5%
LISN alone 294 4% 190 6% 64 6% 3 11% 551 5%
ADH and LISN 32 0% 40 1% 38 4% 1 4% 111 1%
PLCIS 12 0% 2 0% 1 0% 1 4% 16 0%
Total 7204 100% 3107 100% 999 100% 27 100% 11,337 100%
ADH atypical ductal hyperplasia, LISN lobular in situ neoplasia, PLCIS pleomorphic lobular carcinoma in situ.
Table 4. Patterns of breast and distant recurrences following high-, intermediate- and low-grade DCIS.
Primary lesion Ipsilateral Contralateral Unknown side Distant Total Unknown status
nPercent nPercent nPercent nPercent
High-grade DCIS 377 6.6 249 4.3 3 0.05 35 0.4 5753 147
Intermediate-grade DCIS 210 8.2 142 5.6 0 0 8 0.27 2550 63
Low-grade DCIS 73 8.4 39 5.6 1 0.1 3 0.23 868 21
Unknown grade DCIS 3 0% 1 0 0 0 0 0 20 1
Total 663 100% 431 100% 4 100% 46 100% 9191 232
Table 2. Minimum margin size recorded for patients who underwent
breast-conserving surgery (BCS).
Margin size (mm) BCS Percent
0 233 3%
<1 237 3%
1–1.9 614 8%
2–4.9 1559 20%
5–9.9 2015 25%
≥10 2814 35%
Clear 122 2%
Unknown 340 4%
Total 7934 100%
Pathological features of 11,337 patients with primary ductal carcinoma in. . .
AM. Shaaban et al.
4
There was a statistically significantlowerrateofrecurrencefor
lesions with ≥2mm clear margin (p=0.003). Further analysis
showed that the protective effect of the wider margin width was
predominantly on ipsilateral invasive recurrence, both for
patients who received or did not receive radiotherapy (p=
0.03 and 0.04, respectively) and not on subsequent DCIS
recurrence. On analysing margin status and grade of DCIS with
ipsilateral recurrence, margin width had a significant impact on
recurrence for high-grade DCIS but not of intermediate/low-
grade disease. Patients with high-grade DCIS with <2 mm
margin had a 6% recurrence rate (for both in situ and invasive
carcinoma), whereas those with lesions with ≥2 mm margin had
DCIS and invasive recurrence rates of 4 and 5%, respectively.
This difference was statistically significant (p=0.02).
The architecture of the DCIS, the presence of comedo necrosis
and the presence of additional atypia or of microinvasion were
not significantly associated with ipsilateral or contralateral
recurrence.
The rate of distant metastasis as first recurrence, without
evidence of primary invasive disease, was low (28 patients); of
these, 12 (43%) occurred in the first 5 years. The median time to
presentation with distant metastasis was 47.5 months.
Time to subsequent events
Kaplan–Meier survival analysis showed distinct patterns for risk of
ipsilateral events. While the risk of ipsilateral DCIS tailed off after
5 years, the risk of subsequent invasion showed a consistent year
on year increase over 10 years (Fig. 1).
Effect of adjuvant radiotherapy
A protective effect of radiotherapy on recurrence was seen, both
for in situ and invasive ipsilateral carcinoma. Excluding patients
without information on radiotherapy status, recurrence rate for
high-grade DCIS treated with adjuvant radiotherapy was 3.2%
Table 5. Ipsilateral DCIS recurrence and subsequent invasive carcinoma by primary DCIS disease.
Primary lesion Low Intermediate High Unknown Total pvalue
Recurrent DCIS grade
High-grade DCIS 1 1% 16 11% 109 73% 24 16% 150 <0.001
Intermediate-grade DCIS 2 3% 20 34% 22 37% 15 25% 59
Low-grade DCIS 3 19% 3 19% 2 13% 8 50% 16
Total 6 3% 39 17% 133 59% 47 21% 225
Subsequent invasive grade
High-grade DCIS 17 8% 83 39% 79 37% 36 17% 215 0.08
Intermediate-grade DCIS 16 11% 78 53% 35 24% 18 12% 147
Low-grade DCIS 6 12% 28 57% 6 12% 9 18% 49
DCIS unknown grade 0 0% 1 50% 1 50% 0 0% 2
Total 39 9% 190 46% 121 29% 63 15% 413
Cumulative risk of ipsilateral DCIS (BCS only) Cumulative risk of ipsilateral invasive carcinoma (BCS only)
0.08
0.06
0.04
Proportion
0.02
0.00
0.10
0.08
0.06
0.04
Proportion
0.02
0.00
0 5 10 15
7921
Number of risk
7131 2639 0
Analysis time
0 5 10 15
7921
Number of risk
7131 2639 0
Analysis time
0.10
Fig. 1 Risk of development of subsequent ipsilateral DCIS (left) and invasive carcinoma (right) in women receiving breast-conserving
surgery (BCS) by year. The steady increase in risk of invasive disease continues after 10 years of follow-up.
Kaplan meier failure estimate: ipsilateral invasive carcinooma by RT grade (BCS only)
0.20
0.15
0.10
Proportion
0.05
0.00
2061
890
1091
3470
1826
745
1013
3190
698 0
0
0
0
313
410
1133
50
Analysis time
10 15
Number at risk
No RT intermediate/low
No RT intermediate/low
No RT high
No RT high
RT high
RT high
RT low/intermediate
RT low/intermediate
Fig. 2 The effect of radiotherapy (RT) on ipsilateral subsequent
invasive carcinoma in patients treated with breast-conserving
surgery (BCS). Radiotherapy markedly reduced the risk of subsequent
ipsilateral invasive carcinoma in patients with primary high-grade DCIS
and, to a lesser extent, in the low/intermediate-grade category.
Pathological features of 11,337 patients with primary ductal carcinoma in. . .
AM. Shaaban et al.
5
compared to 6.9% without radiotherapy. The recurrent DCIS rates
after low/intermediate-grade DCIS diagnosis with and without
radiotherapy were 2.3 and 3.0%, respectively. Radiotherapy
reduced subsequent invasive carcinoma rates from 8.9 to 3.7%
for high-grade DCIS and from 15 to 7.7% for low/intermediate-
grade DCIS. Patients with high-grade DCIS who did not receive
radiotherapy had the highest rate of subsequent ipsilateral
invasion, whereas those with high-grade DCIS lesions who
received adjuvant radiotherapy had the lowest rate (Fig. 2).
However, when there was such an invasive disease, it was at a
median 56 months following radiotherapy for high-grade DCIS.
This protective effect of radiotherapy persisted after exclusion of
patients who received endocrine therapy (Fig. 1c).
DISCUSSION
This analysis provides an overview of a large, prospective cohort of
well-characterised DCIS diagnosed in women of screening age
within the NHS BSP and is anticipated to be representative of
screen-detected DCIS in general. At its inception, the UK NHS BSP
was available to all women aged 50–64 years but the upper age
limit was increased to age 70 years during 2003–2005. The data
include real-life pathology parameters supplied by the UK Breast
Screening Units that contributed to the Sloane Project and thus
provide a unique opportunity to analyse trends and changes in
DCIS reporting and the clinical management implications over the
course of a decade.
The small but steady increase in DCIS size (from 21.4 to 24.1
mm) over the period was predominantly due to an increase in the
diagnosis of lesions measuring ≥30 mm. This has implications for
surgical management, as the majority of those patients with larger
DCIS underwent mastectomy. Subsequent to this series, onco-
plastic surgical procedures are increasingly being introduced for
large volume lesions, and conversely, fewer patients may now
therefore require mastectomy. The increase in DCIS size identified
between 2003 and 2012 may reflect improvements in imaging
modalities over this time (including the introduction of digital
mammography), together with more extensive sampling of
surgical excision specimens by pathologists, as advised in the
current UK guidelines.
14
Pre-operative assessment guidance now
includes the recommendation for sampling more than one focus
of a mammographically large area of calcification (>30 mm) to
assess the extent of disease, which may also contribute to more
accurate assessment of DCIS size.
18
Over the period presented, there has been an increase in the
proportion of high-grade DCIS (from 59 to 63%) and a decrease in
the diagnosis of low-grade DCIS (from 10 to 6%). While national
guidance on grading has continually been updated,
14
the
consistency of grading of DCIS within the UK External Quality
Assurance Scheme remains only in the moderate range with a
kappa value of 0.55 for high-grade DCIS.
19
Studies from other
countries have shown low consistency in grading but have also
highlighted different distribution of DCIS grades to those seen in
this UK series. For example, in the nationwide Dutch Pathology
Registry, 4952 DCIS reports from 36 laboratories were analysed:
12.5% were reported as low grade (range 6.1–24.4%), 39.5% as
intermediate grade (18.2–57.6%), and 48.0% as high-grade DCIS
(30.2–72.7%).
20
The reasons for the variation in grade of DCIS
between countries and screening programmes remain unclear,
and several international studies of grading reproducibility are
underway to determine whether this predominantly reflects
differences in pathological assessment.
21
An alternative two-tier
grading system (high vs non-high grade) has been proposed;
22
however, one recent international study of 149 DCIS cases
assessed by 39 breast pathologists using such a dichotomous
grading system still showed only moderate agreement (kappa =
0.422).
23
As several worldwide trials are presently being under-
taken of active surveillance vs surgical intervention for low-risk
DCIS,
12
including the LORIS,
9
LORD
10
and the COMET trials
11
, the
reproducible grading of DCIS is increasingly important for clinical
management and methods for improving reproducibility require
further exploration.
In this real-world national prospective data set, only 3% (233) of
patients with BCS had margin clearance described as 0 mm
(‘involved’), with a further 3% having disease <1 mm from the
margin. The UK recommendations of minimum margin clearance
have evolved over the years. Both the latest UK NICE
16
and US
guidelines
17
presently recommend 2 mm clearance for relevant
(circumferential) margins of pure DCIS. This cut-off was being
achieved in at least 80% of the Sloane cohort.
While classical lobular neoplasia and ADH were both most
frequently seen in association with high-grade DCIS (53% of the
total cases with lobular neoplasia as the only other atypical lesion
and 39% of the total cases with ADH alone), this is a reflection of
high-grade DCIS being the most frequently reported grade. As
part of the low nuclear grade neoplasia family,
24
it is not surprising
that additional atypias were proportionately more frequently
associated with intermediate- or low-grade DCIS (12% of total of
lobular neoplasia and 21% of ADH) compared with high-grade
DCIS (4% of lobular neoplasia and 3% of ADH). In a further 111
patients, both ADH and lobular in situ neoplasia were present
along with the DCIS, again more commonly seen with low-grade
DCIS (4% of low-grade DCIS cases) than in intermediate- (1%) or
high-grade disease (<1%).
The reporting of ADH in association with low-grade DCIS is
controversial. ADH is a microfocal, low-grade atypical lesion with
complete involvement of less than two membrane-bound spaces
or <2 mm in extent
15
but is recognised to show similar genetic
and biomarker profiles to low-grade DCIS. Although cytologically
at least part of the spaces will have the features of low-grade DCIS,
this is insufficient in extent for diagnosis of established DCIS.
However, if such partial duct involvement is seen adjacent to a
larger, more established lesion, many would regard the entire
process as low-grade DCIS and not report the two lesions
separately. It is not, however, clear whether in the 611 cases,
where both DCIS and ADH were recorded in the present database,
the processes were in continuity or separate, synchronous lesions.
The co-existence of differing grades of DCIS in an individual
patient has been described, and some even believe that ‘poorly
differentiated’DCIS may evolve from ‘well-differentiated’DCIS by
randomly acquiring genetic defects,
25
although this is not widely
accepted. Other series have shown greater consistency of grade
(85%) in individual patients than uniformity of architecture.
26
In
the Sloane Project, as per UK guidelines, the highest reported
histological grade was recorded but the co-existence of classical
lobular neoplasia and ADH with high-grade DCIS is noteworthy
and merits further investigation of genomic changes present in
these cases.
Microinvasion, defined by the UK NHS BSP surgical reporting
guidelines as one or more invasive foci measuring <1 mm, is a rare
lesion that is recognised to be most commonly seen in the context
of high-grade DCIS.
14
In the present data, it was also identified in
association with intermediate- or low-grade DCIS in 4% of cases;
the recent WHO breast guidelines also highlight this infrequent
existence in non-high-grade lesions.
15
The frequency of micro-
invasion in the present series decreased significantly from 2003/
2004 to 2011/2012, which may reflect adherence to more
stringent criteria for diagnosing microinvasion and the updated
NHS BSP pathology guidelines published in 2005.
27
However,
within the Sloane cohort there was a wide variation in the rate of
reporting of microinvasive carcinoma between centres (0–29%).
This may reflect bias in submission of cases to Sloane from
individual centres, but the incidence of microinvasion in the
literature also varies from as low as 0.68%
28
to as high as 8.3%.
29
The high frequency in some Units submitting data to Sloane also
highlights questions about the reproducibility of this diagnosis.
Pathological features of 11,337 patients with primary ductal carcinoma in. . .
AM. Shaaban et al.
6
The definition of microinvasion as necessarily in the non-
specialised stroma was included in previous UK guidelines
27
but
has been excluded from more recent updated version.
14
Various
definitions have been used (for a review, see Bianchi and
Vezzosi
30
) and the latest WHO book does not include this
criterion.
15
Another histopathological feature that lacks consistency in its
definition and reporting is comedo necrosis; criteria used range
from any central necrosis to expansive necrosis. The definition of
comedo necrosis has been the subject of recent debate,
particularly the minimum amount of central necrosis required to
qualify as ‘comedo necrosis’. One recent survey of 35 experienced
breast pathologists from the USA showed that no single cut-off
was agreed by more than a third of participants;
31
the minimum
threshold of cross sectional necrosis required ranged from 10%
(by 4 pathologists) to 70% (by 1 pathologist). Currently, there is no
clinical evidence for recommending one threshold over any other
and the descriptive term ‘central necrosis’with comment
regarding number, or proportion, of ducts involved may be more
appropriate in describing this histological feature, as recently
recommended by the International Collaboration on Cancer
Reporting DCIS data set.
32
Follow-up data of the patients from England is the largest
component of this prospective cohort. The screening programme
is the same throughout the United Kingdom, and clinical
management guidelines are essentially similar. Therefore, we
believe the data are generalisable to the UK population, as well as
potentially further afield. In the cohort with extended follow-up
(9191 patients), it is intriguing that a higher rate of subsequent
in situ and invasive carcinoma is noted following a primary
diagnosis of either low- or intermediate-grade DCIS compared
with high-grade disease. This is contrary to data from series of
untreated DCIS, where a higher and more rapid rate of
progression to invasive disease is seen for high-grade DCIS left
in situ, i.e. not excised.
33
However, when analysis is limited to the
majority of patients who have undergone BCS (7934, 86% of
patients) the ipsilateral recurrence rates are 9.2, 9.7 and 9.8%,
respectively, for high, intermediate- and low-grade DCIS (with
invasive recurrence frequencies of 4.9, 6.7 and 6.7%, respectively).
More patients with high-grade DCIS undergo mastectomy or
when receiving BCS are in receipt of radiotherapy,
34
which is
known to reduce ipsilateral recurrence.
35
Indeed, an increased
sensitivity of high-grade DCIS to radiotherapy may be deduced
from the present data (Figs. 2and 3), which would contribute to
the lower recurrence rate seen with high-grade DCIS after BCS.
The differences may also be influenced by the ability to determine
DCIS size and especially completeness of excision more accurately
in high-grade DCIS, due to a greater proportion of ducts
associated with microcalcification when compared to low-grade
DCIS in which a greater proportion of the area is non-calcific.
36
Theoretically, for this reason, a greater proportion of low-grade
DCIS may therefore be incompletely excised, albeit unrecognised
on radiological (specimen X-ray) and pathological examination.
In this cohort, the grade of contralateral DCIS or invasive
carcinoma did not necessarily mirror the grade of the primary
DCIS, consistent with contralateral breast cancer representing
independent, new disease, rather than recurrence. Recent
molecular analysis of paired small cohorts of DCIS and invasive
carcinomas within the Sloane cohort supports this hypothesis.
37
While grade of subsequent DCIS was associated with grade of
primary DCIS, the grade of subsequent ipsilateral invasive cancer
showed a non-significant association with the original DCIS grade
(Table 5). Data on the pleomorphism component of the invasive
histological grade is not collected in the Sloane database, but it is
likely that the DCIS cytonuclear grade and pleomorphism score
may show a greater correlation than overall histological invasive
grade.
A novel finding is this study is the tapering of risk of subsequent
ipsilateral DCIS over time, while the risk of invasive carcinoma in
the same breast continued. We believe that this finding is
important and relevant for the need to undertake long-term
follow-up strategies with DCIS and for informed patient decisions
on management. A recent epidemiological study has also
identified that invasive carcinoma continues to develop up to 20
years following the diagnosis and treatment of DCIS.
38
More of the
subsequent events in our series occurred as invasive carcinoma.
This current data therefore differs from earlier reports (e.g.
EBCTCG, EORTC) that recorded that approximately half of the
ipsilateral breast recurrences after a diagnosis of pure DCIS were
as invasive disease and half as DCIS, with a 50% reduction in either
form of recurrence following radiotherapy.
35
This was based on
trials such as NSABP–B17 and EORTC 10853 that included patients
treated between 1985 and 1999. Since then, considerable
advances have been made in refining the radiological and
histological diagnosis, tissue sampling, classification of DCIS and
margin assessment. There has also, however, been progress in
surgical treatment and in revisiting the significance of margin
status, as well as selection of patients for radiotherapy. We believe
that the present data are reflective of current practice, both
histopathological and clinical, and that this change in the nature
of recurrence is likely to be multifactorial.
The main strengths of this study include the prospective
collection of a wide range of pathological features of large
numbers of screen-detected DCIS over time. The link to multiple
national information systems, as well as the provision of
recurrence data from the individual NHS BSP centres, uniquely
allows correlation of the histological features of primary DCIS with
those of subsequent events. However, one caveat in interpreting
these recurrence data is the length of follow-up in these analyses,
given that, even with approaching 10 years of follow-up, further
events are certain to occur in this patient population over
subsequent decades.
In conclusion, we provide a comprehensive overview of the
pathology features of screen-detected DCIS, including information
on recurrence of disease that should inform strategies for DCIS
management, patient counselling and follow-up. The protective
effect of radiotherapy is confirmed on all DCIS grades but is
particularly important in high-grade disease. Issues related to the
reproducibility of some pathological features including comedo
necrosis and microinvasion should be noted; further work to
define the most clinically relevant cut-offs for some features and
subsequent updates to international guidelines are required.
Ipsilateral invasive carcinooma by RT grade (BCS only, no ET)
0.20
0.15
0.10
Proportion
0.05
0.00
1791
757
871
3039
0
0
0
0
1576
629
809
2783
552
256
300
922
50
Analysis time
10 15
Number at risk
No RT intermediate/low
No RT high
RT high
RT low/intermediate
No RT intermediate/low No RT high
RT high
RT low/intermediate
Fig. 3 Ipsilateral invasive recurrence by receipt of radiotherapy
(RT) and grade of DCIS in women who underwent breast-
conserving surgery. Without RT or endocrine therapy (ET ), invasive
carcinoma rates are higher in the high grade than in those with low/
intermediate-grade DCIS up to 10 years.
Pathological features of 11,337 patients with primary ductal carcinoma in. . .
AM. Shaaban et al.
7
While grade of DCIS has previously been of limited clinical
application, the ongoing trials of surveillance of low-risk DCIS have
highlighted the importance of reproducibility of this key
pathological feature.
ACKNOWLEDGEMENTS
This work uses data provided by patients and collected by the UK NHS BSP as part of
their care and support. We thank all patients and all breast units who have
participated in the Sloane Project audit.
AUTHOR CONTRIBUTIONS
B.H., K.C., S.C.: data collection and statistical analysis. A.M.S.: data interpretation,
reviewed the literature, produced first draft of manuscript. S.E.P., A.M.T.: data
interpretation, writing the manuscript, oversaw the Project. E.P., A.M.H., J.S.T., M.G.W.,
E.S.: data interpretation, input and appraisal of manuscript. All authors approved the
final version of the manuscript.
ADDITIONAL INFORMATION
Ethics approval and consent to participate Ethics Committee approval was not
required for this study, originally conducted under the NHS Cancer Screening
Programme’s application to the Patient Information Advisory Group (PIAG). More
recently, the study has been permitted to process personally identifiable data
without consent under Regulation 5 of Statutory Instrument 2002 No. 1438: The
Health Service (Control of Patient Information) Regulations 2002 (15/CAG/0207) in
line with the following clause: ‘quality assuring screening services to ensure they are
effective and safe, and that any incidents are investigated and managed
appropriately’. This statutory exemption to common law permits Public Health
England to process personally identifiable data for activities it is ‘responsible and
accountable to the Secretary of State for Health for’, as part of its core remit for
population screening.
Consent to publish All authors gave consent for publication.
Data availability Data are held by Public Health England. Access to the Sloane
Project data from external parties is governed by consultation with the Sloane Project
Steering Group and application to Public Health England’s breast screening research
advisory committee (RAC) and Public Health England’soffice for data release (ODR).
Data will subsequently only be released by Public Health England to researchers
under approval and in an anonymised or depersonalised format, with a data sharing
contract in place.
Competing interests The authors declare no competing interests.
Funding information This work was supported by Public Heath England and, in part,
by Cancer Research UK and by KWF Kankerbestrijding (ref. C38317/A24043) who
provided funding support for K.C., E.S., A.M.T. and S.E.P.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims
in published maps and institutional affiliations.
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