
==== Front
Breast
Breast
The Breast : Official Journal of the European Society of Mastology
0960-9776
1532-3080
Elsevier

S0960-9776(24)00138-3
10.1016/j.breast.2024.103807
103807
Review
Atypical ductal or lobular hyperplasia, lobular carcinoma in-situ, flat epithelial atypia, and future risk of developing breast cancer: Systematic review and meta-analysis
Baker Jannah jannah.baker@sydney.edu.au
a⁎
Noguchi Naomi b
Marinovich M Luke ab
Sprague Brian L. c
Salisbury Elizabeth de
Houssami Nehmat ab
a The Daffodil Centre, University of Sydney, a Joint Venture with Cancer Council NSW, Sydney, Australia
b School of Public Health, Faculty of Health and Medicine, University of Sydney, Sydney, NSW, Australia
c Departments of Surgery and Radiology, University of Vermont Cancer Center, Burlington, VT, USA
d University of Sydney, Western Clinical School, Westmead Hospital, NSW, Australia
e Department of Tissue Pathology and Diagnostic Oncology, ICPMR, NSW Health Pathology, Westmead Hospital, NSW, Australia
⁎ Corresponding author. Daffodil Centre, University of Sydney Camperdown, Sydney, New South Wales, 2050, Australia. jannah.baker@sydney.edu.au
11 9 2024
12 2024
11 9 2024
78 10380724 6 2024
26 8 2024
7 9 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

Biopsy-proven breast lesions such as atypical ductal hyperplasia (ADH) or atypical lobular hyperplasia (ALH), lobular carcinoma in situ (LCIS) and flat epithelial atypia (FEA) increase subsequent risk of breast cancer (BC), but long-term risk has not been synthesized. A systematic review was conducted to quantify future risk of breast cancer accounting for time since diagnosis of these high-risk lesions.

Methods

A systematic search of literature from 2000 was performed to identify studies reporting BC as an outcome following core-needle or excision biopsy histology diagnosis of ADH, ALH, LCIS, lobular neoplasia (LN) or FEA. Meta-analyses were conducted to estimate cumulative BC incidence at five-yearly intervals following initial diagnosis for each histology type.

Results

Seventy studies reporting on 47,671 subjects met eligibility criteria. BC incidence at five years post-diagnosis with a high-risk lesion was estimated to be 9.3 % (95 % CI 6.9–12.5 %) for LCIS, 6.6 % (95 % CI 4.4–9.7 %) for ADH, 9.7 % (95 % CI 5.3–17.2 %) for ALH, 8.6 % (95 % CI 6.5–11.4 %) for LN, and 3.8 % (95 % CI 1.2–11.7 %) for FEA. At ten years post-diagnosis, BC incidence was estimated to be 11.8 % (95 % CI 9.0–15.3 %) for LCIS, 13.9 % (95 % CI 7.8–23.6 %) for ADH, 15.4 % (95 % CI 7.2–29.3 %) for ALH, 17.0 % (95 % CI 7.2–35.3 %) for LN and 7.2 % (95 % CI 2.2–21.2 %) for FEA.

Conclusion

Our findings demonstrate increased BC risk sustained over time since initial diagnosis of high-risk breast lesions, varying by lesion type, with relatively less evidence for FEA.

Highlights

• Cumulative breast cancer risk varies by time from initial lesion and by lesion type.

• Moderate/high breast cancer risk shown within 10 years from initial high-risk lesion.

• There is relatively less evidence of breast cancer risk after flat epithelial atypia.

Keywords

Breast cancer
Atypical proliferations
Breast cancer risk
Lobular carcinoma in-situ
Mammography
Biopsy
==== Body
pmc1 Introduction

Female breast cancer (BC) is the most commonly diagnosed cancer and fifth leading cause of cancer mortality worldwide, accounting for 2.3 million new cases of cancer and 685,000 cancer-related deaths in 2020 [1]. Among women, it accounts for 1 in 4 new cases of cancer and 1 in 6 cancer deaths, with rising incidence in both high-income and transitioning countries [2].

Biopsy-proven diagnoses of atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS) increase the risk of subsequent breast cancer in women, with various studies reporting a 3–5 times greater risk for ADH and ALH [[3], [4], [5]] and 4–10 times for LCIS [6,7] compared with women with non-proliferative disease. Although molecular studies also describe a potential role of flat epithelial atypia (FEA) as a precursor to malignancy [8,9], the association between biopsy-proven FEA in women and their subsequent risk of developing BC is less well-defined, leading to uncertainty about their management. BC risk following a diagnosis of severe ADH, described to have features in between ADH and ductal carcinoma in situ (DCIS) [10], is also unclear.

Although several retrospective cohort and case-control studies have examined the association between ADH, ALH, LCIS and FEA and risk of subsequent BC, there is a lack of a comprehensive review summarising the findings of these studies and accounting for time since diagnosis by lesion histology type. Although one review from 2015 summarised the relative risk of BC following diagnosis with ADH and/or ALH combined, this had some limitations [11], including not accounting for differing follow-up time after the initial diagnosis, and not distinguishing between ALH and ADH in pooled analysis. There remains uncertainty in ongoing management of women with biopsy-proven high-risk lesions due to a lack of robust evidence on BC risk in this population [12,13]. These high-risk breast lesions may also be referred to as atypical proliferations, preneoplasia, or B3 (lesions with uncertain malignant potential) when diagnosed at core needle biopsy [[14], [15], [16]].

Given this clinical uncertainty and emerging interest in risk-adapted screening, there is a need for a comprehensive systematic review summarising evidence particularly from more recent studies, reflecting that many of these lesions are diagnosed on core needle biopsies as part of mammographic screening [17]. This systematic review and meta-analysis aims to address the above-mentioned evidence gaps by estimating future risk of breast cancer specific to ALH, ADH, LCIS and FEA, adjusting for follow-up time from date of diagnosis of these risk-related breast lesions.

2 Material and methods

2.1 Search strategy

A systematic review was conducted to identify all articles published between January 2000 to September 2023 reporting breast cancer incidence or risk following a biopsy-proven diagnosis of ADH, ALH, LCIS and/or FEA, as per our pre-registered protocol [18]. Systematic searches were performed using MEDLINE via Ovid, Scopus, Cochrane Library, CINAHL Complete and Google Scholar. Searches were limited to English language, human studies and publication date from 2000 onwards. The search strategy was formulated based on keywords from a preliminary literature search and with guidance from experts in the field, and the search terms were tailored to each database. The search strategy for MEDLINE and CINAHL is reported in Supplementary Table 1. Reference lists of primary and review articles were also examined for additional relevant studies.

2.2 Study selection

Selection criteria were defined prior to undertaking electronic searches. We included cohort studies, case control studies and randomised controlled trials (RCT) reporting data on women diagnosed by core needle or excisional biopsy with ADH, ALH, LCIS, FEA, lobular neoplasia (LN, a combination of ALH and LCIS) or severe ADH. Only studies reporting outcomes for twenty or more women with the same lesion histology type were included. Studies were included if patients were female and aged eighteen years and over, and if they reported data on the number, rate, overall incidence (for the entire study duration), cumulative incidence (for specific follow-up periods), odds ratio (OR), risk ratio or hazard ratio of breast cancer development (invasive or DCIS) at follow-up. Studies were excluded if patients had a previous diagnosis of breast cancer or any other type of cancer, or if their diagnosis was cytology-rather than biopsy-based. Patients reported to have been upgraded (upstaged) to malignancy on excision were excluded from this review. Data for patients not taking chemoprevention was extracted from studies that described results for both women taking and not taking chemoprevention. Where more than one article was found describing the same study with overlapping enrolment dates, only the most complete publication (i.e. with the largest sample size) was included.

After a pilot screen of ten randomly selected studies, two authors (J.B. and N.N.) independently performed title and abstract screening for a random subset comprising 20 % of studies. Disagreements were resolved by discussion, or where needed, by arbitration by a third author (M.L.M.). Following this, the first reviewer (J.B.) undertook title and abstract screening for the remainder of the studies. Full text articles of potentially eligible studies were retrieved, and a random subset of 20 % were independently reviewed against eligibility criteria by two authors (J.B. and N.N.). Disagreements were resolved by discussion, and where needed, arbitration by two other authors (M.L.M. and N.H.). The first reviewer (J.B.) subsequently completed full manuscript review for the remainder of studies.

2.3 Data extraction and quality assessment

One reviewer (J.B.) completed data extraction from each included study, and all data were checked by another reviewer (N.N.). Where studies disaggregated patients that did and did not meet selection criteria, only information about patients fulfilling the criteria was extracted. For each included study, information was extracted about study design, country, setting, databases used, number of women diagnosed with each benign histological category, time period and type of initial biopsy (e.g. core needle, excisional). We extracted summary statistics for follow-up time and age of patients, types of breast cancer reported as outcomes (e.g. invasive, DCIS), type of outcome measures reported and breast cancer risk, and any stratification of results by covariates such as age group or specific management where applicable.

The quality of included studies was assessed using the Newcastle Ottawa Scale (NOS) for cohort and case control studies, modified for our study question [19]. Randomised controlled trials (RCTs) reporting on the population and outcome of interest over the trial follow-up period were treated as cohort studies nested within RCTs. For Outcome criterion 2, a threshold of five years or more average follow-up was used, and for Outcome criterion 3, a threshold of ≥80 % retained throughout the follow-up period was used. Quality appraisal was performed by one reviewer (J.B.), and results for a random 20 % of included studies were checked by a second reviewer (M.L.M.). For included cohort studies including those nested within RCTs, the second Selection criterion (selection of the non-exposed cohort) and Comparability criterion were omitted from our scoring due to the lack of relevancy of a comparison group when assessing the incidence of BC risk for any particular histology group. Therefore, cohort studies could achieve a maximum score of three (rather than the usual four) for the Selection criteria.

2.4 Statistical analysis

Results were summarised individually by histological category across studies reporting similar outcome measures, which included 5-, 10-, 15- and 20-year cumulative incidence, and overall incidence for the entire study duration adjusted for average follow-up time. Risk associations reported as odds ratios, relative risk, hazard ratios and incidence rate ratios were extracted and described in summary tables. For cumulative and overall incidence, the mean proportion of women developing breast cancer with 95 % Clopper-Pearson confidence intervals (CIs) was computed using the number of events and total number of women at risk reported by the study and presented in Forest plots (‘rmeta’ in R version 4.3.1) [20].

Wherever three or more studies reported an outcome measure for a specific histologic category, a generalised linear mixed meta-analysis model with random-effects for study was fit to pool estimates (using the ‘glimmix’ procedure in SAS Enterprise Guide software version 7.1). I2 statistics were computed to quantify statistical heterogeneity between studies with similar follow-up length and outcome measures.

For studies reporting overall incidence, varying follow-up times were adjusted for using random effects logistic meta-regression models with average follow-up time as a covariate for each study. Using these models, the estimated incidence for each histological category at five and ten years following diagnosis was computed with 95 % CIs. The average time was the mean or median follow-up time for each histological category where reported, or for the entire study. Only studies reporting average follow-up time, as well as number of women developing breast cancer and number of women at risk, were able to be included in meta-regression models. Details of studies that could not be included are summarised in Supplementary Table 2. Models considering linear and quadratic functions for the effect of follow-up time were compared using −2 residual log pseudo-likelihood and generalised chi-squared measures/degrees of freedom measures of goodness of fit (linear models were found to have the best fit and are reported here). Sensitivity analyses were conducted for overall incidence of breast cancer (invasive breast cancer (IBS) and DCIS) excluding studies that examined IBC only or ipsilateral IBC and DCIS only.

3 Results

An overview of study inclusion process and reasons for study exclusion are presented in the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [21] diagram in Fig. 1. Seventy studies met eligibility criteria [[3], [4], [5], [6],10,17,[22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85]], providing data on a total of 47,671 subjects. Included studies comprised 61 retrospective cohort studies, two RCTs and seven case control studies. Characteristics of included studies are summarised in Supplementary Table 3; details of biopsies, pathological review and radiological findings for the subset of studies providing this information are in Supplementary Table 4. Twelve studies reported including screening populations [5,10,25,28,30,31,37,48,55,63,73,77], but most studies did not specify this information. All studies reported on bilateral BC risk, apart from two [10,58] that reported on ipsilateral risk.Fig. 1 PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) diagram of study selection process Footnote: ADH = atypical ductal hyperplasia, ALH = atypical lobular hyperplasia, LCIS = lobular carcinoma in situ, FEA = flat epithelial atypia, RCT = randomised controlled trial.

Fig. 1

3.1 Lobular carcinoma in situ

3.1.1 Cumulative incidence reported in primary studies

Cumulative incidence of IBC or DCIS following initial diagnosis of LCIS was reported at five-, ten-, fifteen- and twenty-years by six [34,38,45,55,77,81], six [26,38,45,55,77,81], three [38,77,81] and three [38,77,81] studies respectively, including a report of number of events and numbers at risk (Fig. 2). One study reported cumulative incidence of IBC only [77] while the remainder reported cumulative incidence of IBC and DCIS combined. Pooled estimates for cumulative breast cancer incidence following LCIS diagnosis were 7.0 % (95 % CI 2.7–16.7 %) for five-year, 11.3 % (95 % CI 10.5–12.1 %) for ten-year, 16.4 % (95 % CI 12.5–21.5 %) for fifteen-year, and 19.7 % (95 % CI 16.7–23.1 %) for twenty-year incidence (Fig. 2). Heterogeneity was observed between studies for five- (I2 = 86 %) and ten-year cumulative incidence (I2 = 58 %) but not for fifteen- and twenty-year cumulative incidence (I2 = 0 % for both).Fig. 2 Cumulative incidence of breast cancer following biopsy-proven diagnosis of lobular carcinoma in situ. Footnote: *Reported outcome is invasive breast cancer but not ductal carcinoma in situ. n = number of breast cancer cases, N = number of women at risk, CI = confidence interval.

Fig. 2

An additional two studies reported cumulative incidence at ten years (estimated at 14.9 % (95 % CI 13.0–17.0 %) and 23.7 % (95 % CI not reported)) [34,78], and another two reported cumulative incidence at twenty years (estimated at 25.9 % (95 % CI 22.9–29.0 %) and 27.5 % (95 % CI not reported)) [45,78]. However, these studies did not report the number of events and numbers at risk at these time points and were thus excluded from meta-analyses. Only one study was found reporting 25- and 30-yr cumulative incidence following LCIS, which was estimated to be 22.8 % (95 % CI 20.6–25.1 %) and 25.8 % (95 % CI 22.1–29.8 %) respectively [81].

3.1.2 Modelled incidence from meta-regression

Twenty-one studies reporting overall incidence of breast cancer with varying average follow-up times after initial LCIS diagnosis were included in meta-regression (Fig. 3) [6,25,26,28,32,34,38,39,42,44,45,47,[55], [56], [57], [58],64,68,70,74,77,78,81,85]. Of these, sixteen reported incidence of IBC and DCIS combined, four reported incidence of IBC only [6,39,47,77], and one study reported incidence of ipsilateral IBC and DCIS combined [58]. Modelled incidence was estimated to be 9.3 % (95 % CI 6.9–12.5 %) at five years, and 11.8 % (95 % CI 9.0–15.3 %) at ten years following LCIS diagnosis. Data were extracted for classic LCIS, apart from one study with 25 cases of non-classic LCIS (this study was excluded in sensitivity analyses) [58].Fig. 3 Overall incidence of breast cancer following biopsy-proven diagnosis of lobular carcinoma in situ (LCIS) or lobular neoplasia (LN), and estimated 5- and 10-year cumulative risk from meta-regression models. Reported follow-up for each study is the average follow-up period. Footnote: *Reported outcome is invasive breast cancer but not ductal carcinoma in situ. **Reported outcome is ipsilateral invasive breast cancer or ductal carcinoma in situ, and study included non-classic LCIS. n = number of breast cancer cases, N = number of women at risk, CI = confidence interval, LCIS = lobular carcinoma in situ, BC = breast cancer, LN = lobular neoplasia, ALH = atypical lobular hyperplasia.

Fig. 3

3.1.3 Comparative estimates

One retrospective cohort study compared IBC risk following LCIS diagnosis to the risk for women with non-proliferative disease on biopsy [6], with an estimated OR of 4.51 (95 % CI 3.18–6.41, Table 1) and relative risk of 4.24 (95 % CI 3.07–5.87, Table 2). Another study reported a hazard ratio 95 % CI of 3.03–18.66 (mean estimate not reported) for BC-free survival following LCIS diagnosis compared with a control group with fibrocystic changes [64] (Table 3).Table 1 Summary of studies reporting odds ratio estimates of breast cancer risk for women with LCIS, ADH or ALH, by histology type.

Table 1Study	Comparator	Mean/median follow-up	Group with ADH/ALH/LCIS	Comparator group	Odds ratio (95 % CI)	
BC cases	Non-BC cases	BC cases	Non-BC cases	
LCIS	
Kerlikowske 2017a	Non-proliferative disease	Median 8.3yrs for all BBD cases	36	433	535	29038	4.51 (3.18–6.41)*	
ADH	
Kabat 2010	Non-proliferative disease	Mean 15.4 years for all BBD cases	13	6	190	250	2.50 (0.49–12.87)**	
Collins 2016	Non-proliferative disease	Not reported	53	120	108	680	3.20 (2.10–4.70)**	
Worsham 2009	Non-proliferative disease	Not reported	22	22	48	234	4.88 (2.50–9.50)*	
Shaaban 2002	Non-proliferative disease	Mean 5.6 years for all histology types	7	11	9	42	2.97 (0.90–9.76)*	
ALH	
Kabat 2010	Non-proliferative disease	Mean 15.4 years for all BBD cases	16	5	190	250	8.00 (1.00–63.96)**	
Collins 2016	Non-proliferative disease	Not reported	55	55	108	680	6.60 (4.20–10.30)**	
Worsham 2009	Non-proliferative disease	Not reported	10	9	48	234	5.42 (2.09–14.04)*	
Shaaban 2002	Non-proliferative disease	Mean 5.6 years for all BBD cases	10	7	9	42	6.67 (2.00–22.24)*	
ADH or ALH	
Kerlikowske 2017a	Non-proliferative disease	Median 8.3yrs for all BBD cases	59	1721	535	29573	1.90 (1.44–2.49)*	
Arthur 2017	No lesion or non-proliferative lesion	9+ years	31	7	87	114	6.13 (2.46–15.24)**	
Shaaban 2002	Non-proliferative disease	Mean 5.6 years for all BBD cases	17	18	9	42	4.41 (1.66–11.73)*	
Byrne 2001	Non-proliferative disease	Not reported	58	41	62	94	2.14 (1.28–3.58)*	
Poola 2019	Non-atypical BBD	Not reported	74	75	88	203	2.28 (1.51–3.42)*	
Tice 2013	Non-proliferative disease	Median 6.1 years for all BBD cases	136	1838	792	29138	2.72 (2.26–3.29)*	
LCIS = lobular carcinoma in situ, BC = breast cancer, CI = confidence interval, BBD = benign breast disease, ADH = atypical ductal hyperplasia, ALH = atypical lobular hyperplasia.

Table 2 Summary of studies reporting relative risk estimates of breast cancer risk for women with LCIS, ADH or ALH, by histology type.

Table 2Study	Comparator	Mean/median follow-up	Group with ADH/ALH/LCIS	Comparator group	Relative risk (95 % CI)	
BC cases	Non-BC cases	BC cases	Non-BC cases	
LCIS	
Kerlikowske 2017a	Non-proliferative disease	Median 8.3 years for all BBD cases	36	433	535	29038	4.24 (3.07–5.87)	
ADH	
Worsham 2007	Non-proliferative disease	>6 months	23	156	48	1701	4.68 (2.92–7.51)	
ALH	
Worsham 2007	Non-proliferative disease	>6 months	6	61	48	1701	3.26 (1.45–7.36)	
ADH or ALH	
Cote 2012	Non-proliferative disease	Median 10.1 years for all BBD	5	39	33	912	3.25 (1.34–7.93)	
Tice 2015	Non-proliferative disease	Median 6.1 years for all BBD cases	136	1838	792	29138	2.60 (2.18–3.11)	
Hartmann 2005	Non-proliferative disease	Median 15 years for all biopsy results	64	272	379	5682	3.05 (2.39–3.88)	
Castells 2015	Non-proliferative disease	Median 6.1 years for all BBD cases	6	153	114	4634	1.57 (0.70–3.52)	
Kerlikowske 2017a	Non-proliferative disease	Median 8.3 years for all BBD cases	59	1662	535	29038	1.90 (1.45–2.47)	
Louro 2021	Non-proliferative disease	>2 years	13	375	177	7053	1.37 (0.79–2.38)	
LCIS = lobular carcinoma in situ, BC = breast cancer, CI = confidence interval, ADH = atypical ductal hyperplasia, ALH = atypical lobular hyperplasia, BBD = benign breast disease. aOutcome was invasive breast cancer only.

Table 3 Summary of studies reporting hazard ratio estimates of breast cancer risk for women with LCIS, ADH or ALH, by histology type.

Table 3Study	Comparator	Mean/median follow-up	Group with ADH/ALH/LCIS	Comparator group	Hazard ratio (95 % CI)	
N	N	
LCIS	
Renshaw 2016	Fibrocystic changes	Mean 7.4 years	69	100	(3.03–18.66)	
ADH	
Renshaw 2016	Fibrocystic changes	Mean 6.3 years	175	100	(1.09–7.30)	
ALH	
Page 2003	Non-proliferative disease	>6 months	166	7336	2.6 (1.7–3.9)	
ADH or ALH	
Louro 2021	No BBD	>2 years	388	7230	3.82 (2.23–6.56)	
LCIS = lobular carcinoma in situ, CI = confidence interval, ADH = atypical ductal hyperplasia, ALH = atypical lobular hyperplasia, BBD = benign breast disease.

3.2 Atypical ductal hyperplasia

3.2.1 Cumulative incidence reported in primary studies

Two studies reported five-year cumulative incidence of IBC and DCIS following initial diagnosis with ADH. Of these, one reported that among 129 cases of pure ADH, four cases of breast cancer occurred within five years (estimated five-year cumulative incidence of 3.1 %) [36]. The second study reported that of 713 ADH cases present at the start of the study, cumulative incidence of breast cancer was 4.5 % at five years and 17.3 % at ten years [34]. A third study reported a ten-year cumulative incidence of 5.7 % (95 % CI 4.3–10.1 %) following ADH [17]. However, these studies did not report how many women were still at risk vs. lost to follow-up after five or ten years of follow-up.

3.2.2 Modelled incidence from meta-regression

Fifteen studies reported overall incidence of IBC and DCIS following ADH; twelve were included in meta-regression (Fig. 4) [23,27,32,[34], [35], [36],40,43,64,67,68,84]. Incidence was estimated to be 6.6 % (95 % CI 4.4–9.7 %) at five years, and 13.9 % (95 % CI 7.8–23.6 %) at ten years following ADH diagnosis. Details of studies that could not be included in meta-regression models are reported with references in Supplementary Table 2 for each histology type.Fig. 4 Overall incidence of breast cancer following biopsy-proven diagnosis of atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), or ADH and/or ALH combined, and estimated 5- and 10-year cumulative risk from meta-regression models. Reported follow-up for each study is the average follow-up period. Footnote: *Reported outcome is invasive breast cancer but not ductal carcinoma in situ. n = number of breast cancer cases, N = number of women at risk, CI = confidence interval, ADH = atypical ductal hyperplasia, BC = breast cancer, ALH = atypical lobular hyperplasia.

Fig. 4

3.2.3 Comparative estimates

Four studies reported OR estimates for breast cancer ranging from 2.5 to 4.9 following ADH diagnosis compared with women with non-proliferative disease on biopsy (Table 1) [33,41,69,83]. One study reported a relative risk of 4.7 (Table 2) and incidence rate ratio of 5.0 (95 % CI 2.3–11.0) compared with non-proliferative disease [82]. Another study reported a hazard ratio 95 % CI of 1.09–7.30 (mean estimate not reported) for BC-free survival following ADH diagnosis compared with a control group with fibrocystic changes [64] (Table 3).

3.3 Severe ADH

3.3.1 Cumulative incidence reported in primary studies

Two studies reported five- or ten-year cumulative incidence of breast cancer following initial diagnosis of severe ADH. Of these, the first reported a five-year cumulative incidence of 9.7 % and ten-year cumulative incidence of 26 % for IBC and DCIS out of 161 cases of severe ADH present at the start of the study [34]. The second study reported a five-year cumulative incidence of 7.7 % for ipsilateral IBC and DCIS combined only, out of 143 cases of severe ADH at the start of the study [10].

3.3.2 Overall incidence

Two studies reported overall incidence of breast cancer following diagnosis of severe ADH. The first, with a mean follow-up of 5.7 years, reported 21 IBC and DCIS cases combined out of 161 cases of severe ADH among women not treated with chemotherapy (overall incidence of 13.0 %) [34]. The second, with a median follow-up of 2.9 years, reported ipsilateral IBC or DCIS only, with eleven cases out of 143 women initially diagnosed with severe ADH (overall incidence of 7.7 %) [10].

3.3.3 Comparative estimates

No studies reported comparative estimates of breast cancer risk among women with severe ADH compared to a control population.

3.4 Atypical lobular hyperplasia

3.4.1 Cumulative incidence reported in primary studies

One study reported five-year cumulative incidence following ALH diagnosis [34]. Of 488 women diagnosed with ALH at the start of the study, a five-year cumulative incidence of 20.7 % was reported for IBC and DCIS combined.

3.4.2 Modelled incidence from meta-regression

Eight studies reported overall incidence of IBC and DCIS following ALH, and six were included in meta-regression models (Fig. 4) [32,34,35,42,68,71]. Incidence was estimated to be 9.7 % (95 % CI 5.3–17.2 %) at five years, and 15.4 % (95 % CI 7.4–29.3 %) at ten years following ALH diagnosis.

3.4.3 Comparative estimates

Four studies reported the OR of breast cancer following ALH compared with women with non-proliferative disease on biopsy, with estimates ranging from 5.4 to 8.0 (Table 1) [33,41,69,83]. One study reported a relative risk of 3.3 (Table 2) and incidence rate ratio of 3.2 (95 % CI 0.8–12.4) compared with non-proliferative disease [82]. Another study reported a hazard ratio of 2.6 (95 % CI 1.7–3.9) for BC-free survival following ALH diagnosis compared with a control group with non-proliferative disease [60] (Table 3).

3.5 ADH and/or ALH combined

3.5.1 Cumulative incidence reported in primary studies

For ADH and/or ALH combined into one group, one study reported a five-year cumulative incidence of 7.6 % (95 % CI 5.9–9.3 %), ten-year cumulative incidence of 25.1 % (95 % CI 20.7–29.2 %) and fifteen-year cumulative incidence of 40.1 % (95 % CI 32.8–46.6 %) for IBC and DCIS amongst 1353 cases of AH [50]. Another study reported a five-year cumulative incidence of 3.3 % and ten-year cumulative incidence of 13.5 % for IBC and DCIS amongst 1088 cases present at the start of the study [76]. A third study reported a ten-year cumulative incidence of 9.4 % with 31 cases of IBC or DCIS out of 331 women at risk at ten years [29].

3.5.2 Modelled incidence from meta-regression

Fifteen studies reported overall incidence of IBC and DCIS following ADH and/or ALH combined. Meta-regression of thirteen studies reporting the average follow-up time and number of breast cancer cases estimated incidence of 6.0 % (95 % CI 4.1–8.7 %) at five years, and 10.3 % (95 % CI 7.2–14.4 %) at ten years following AH diagnosis (Fig. 4) [3,5,6,25,32,34,35,46,68,75,79,80,85].

3.5.3 Comparative estimates

Four studies reported odds ratio of breast cancer following ADH and/or ALH combined, ranging from 1.9 to 4.4 vs. women with non-proliferative disease (Table 1) [6,31,69,75]. One study reported an OR of 6.1 vs. women with either no lesion or non-proliferative disease [24], and one reported an OR of 2.3 vs. non-atypical benign breast disease [61] (Table 1). Six studies reported risk ratios ranging from 1.4 to 3.3 vs. women with non-proliferative disease (Table 2) [[3], [4], [5], [6],48,76]. One study reported a hazard ratio of 3.8 (95 % CI 2.2–6.6) for BC-free survival following ADH and/or ALH diagnosis compared with a control group without benign breast disease [48] (Table 3).

3.6 Lobular neoplasia

3.6.1 Cumulative incidence reported in primary studies

No studies reported cumulative BC incidence at five or more years following LN diagnosis.

3.6.2 Modelled incidence from meta-regression

Fourteen studies reported overall incidence of IBC and DCIS following LN and were included in meta-regression (Fig. 3) [27,28,32,34,36,42,44,51,52,57,63,68,72,73]. Modelled incidence was estimated to be 8.6 % (95 % CI 6.5–11.4 %) at five years, and 17.0 % (95 % CI 7.2–35.3 %) at ten years following ADH diagnosis.

3.6.3 Comparative estimates

No studies reported comparative estimates of breast cancer risk among women with LN compared to a control population.

3.7 ADH, ALH and/or LCIS combined

Two studies reported overall incidence of BC following a diagnosis of ADH, ALH or LCIS, and did not distinguish between these histology types in reported results. With average follow-up time of 7.5 and 7.7 years respectively, reported BC incidence varied widely between these two studies at an estimated 18.9 % and 3.5 % respectively (Supplementary Table 2) [22,53].

3.8 Flat epithelial atypia

3.8.1 Cumulative incidence reported in primary studies

No studies reported cumulative BC incidence at five or more years following FEA diagnosis.

3.8.2 Modelled incidence from meta-regression

Seven studies reported overall incidence of IBC or DCIS following a diagnosis of FEA; six of these reported sufficient data to be included in meta-regression models (Fig. 5) [27,49,54,59,65,66]. Modelled incidence was 3.8 % (95 % CI 1.2–11.7 %) at five years, and 7.2 % (95 % CI 2.2–21.2 %) at ten years following FEA diagnosis.Fig. 5 Overall incidence of breast cancer following biopsy-proven diagnosis of flat epithelial atypia (FEA), and estimated 5- and 10-year cumulative risk from meta-regression models. Reported follow-up for each study is the average follow-up period. Footnote: *Reported outcome is invasive breast cancer but not ductal carcinoma in situ. n = number of breast cancer cases, N = number of women at risk, CI = confidence interval, FEA = flat epithelial atypia, BC = breast cancer.

Fig. 5

3.8.3 Comparative estimates

No studies reported comparative estimates of breast cancer risk among women with FEA compared to a control population.

3.9 Sensitivity analysis

Studies that examined IBC only, or ipsilateral IBC and DCIS only, or non-classic LCIS were excluded for each relevant histology type in sensitivity analyses. Five studies were excluded for LCIS, resulting in slightly higher mean estimates for 5-year incidence (11.0 % (95 % CI 7.9–15.2 %) for sensitivity analysis vs. 9.3 % (95 % CI 6.9–12.5 %) from main analysis), and 10-year incidence (12.7 % (95 % CI 9.3–17.2 %) for sensitivity analysis vs. 11.8 % (95 % CI 9.0–15.3 %) from main analysis).

One study was excluded for ADH and/or ALH combined, also leading to higher mean estimates for 5-year incidence (6.5 % (95 % CI 4.6–9.0 %) for sensitivity analysis vs. 6.0 % (95 % CI 4.1–8.7 %) from main analysis), and 10-year incidence (11.3 % (95 % CI 8.2–15.3 %) for sensitivity analysis vs. 10.3 % (95 % CI 7.2–14.4 %) from main analysis). One study was excluded for FEA, with higher mean estimates for 5-year incidence (5.5 % (95 % CI 1.9–14.4 %) for sensitivity analysis vs. 3.8 % (95 % CI 1.2–11.7 %) from main analysis), and 10-year incidence (8.5 % (95 % CI 3.2–20.4 %) for sensitivity analysis vs. 7.2 % (95 % CI 2.2–21.2 %) from main analysis).

3.10 Quality assessment results

Study-specific ratings are presented in Supplementary Table 5, a summary of scores for cohort studies and RCTs in Supplementary Fig. 1 and for case control studies in Supplementary Fig. 2.

Cohort studies and RCTs (N = 63) were least likely to meet NOS criterion for Outcome 2 (follow-up length ≥5 years, 37 % did not meet criteria). Roughly a quarter of studies did not meet Selection 1 (representativeness of cohort) and Selection 3 (description of how exposure was ascertained) criteria. Case control studies were least likely to meet Exposure 3 criterion (details of non-response rate, 43 % did not meet criteria).

4 Discussion

This systematic review summarises the intermediate and long-term risk of developing breast cancer among women with ADH, ALH, LCIS, LN and FEA. It is the first systematic review to estimate BC risk specific to histology type while accounting for time since diagnosis of these high-risk breast lesions. We have summarised studies reporting cumulative risk at five-yearly intervals up to thirty years post-biopsy where available. Furthermore, we have reported pooled results of overall incidence accounting for varying follow-up time using meta-regression models to provide estimates of five- and ten-year BC risk by histology type of these lesions. Our findings provide precise estimates for discussion of risk-adapted screening and prevention with women who have been diagnosed with these lesions.

We estimate high cumulative incidence at 10-years (11.3 %) and at 20-years (19.7 %) for LCIS, and similarly for lobular neoplasia (LCIS and ALH) with 10-year incidence of 17 %. To put these into context, US guidelines for breast cancer screening deﬁne high risk as a lifetime risk of breast cancer ≥20 % [86], while we show estimates approximating this at 10–20 year follow-up of women with these breast lesions. Estimated 10-year BC incidence following ADH and ALH is also high, at 13.9 % for ADH and 15.4 % for ALH. Notably, lifetime risk calculators recommended by US screening guidelines (NCCN, ACS) are largely based on family history of breast cancer and may not identify women with LCIS, ALH or ADH as appropriate for supplemental MRI screening.

There is relatively less evidence of BC risk following FEA with estimated 10-year incidence of 7.2 %. The atypia present in FEA pathology can be subtle, and these lesions were formally recognised as “flat epithelial atypia” only in 2003 by the World Health Organization [23]. This is reflected in the small number of studies available examining FEA. In comparison, diagnostic criteria for LCIS, ADH and ALH have remained stable for over thirty years, with more evidence of BC risk available.

One previous systematic review summarised the relative risk of developing BC following diagnosis with AH, including studies with data through 1987 to 2010 [11]. Our review expands on this prior work by reporting on measures of cumulative and overall incidence, accounting for differing follow-up time, comparator group, and use of odds vs relative risk ratios in included studies. We were also able to distinguish between ADH and ALH in most analyses, quantify BC incidence by time since initial diagnosis and include more recent studies. We focused on literature from 2000 onwards given that clinical practices for screening and diagnosis have progressively changed since the turn of the century, with use of screening mammograms and core needle biopsies to evaluate non-palpable lesions becoming more widespread [17]. Our systematic review is also the first to pool estimates separately for ADH and ALH, and include estimates for LCIS, LN and FEA. Furthermore, when extracting study data, we ensured that data representing upgraded cases were not included in the analyses, ensuring our estimates represent future risk of breast cancer.

For most lesion types apart from LCIS, insufficient study data was available to combine reported cumulative incidence estimates. Although most studies reported on occurrence of IBC and DCIS combined, a few reported only on IBC, or only on ipsilateral IBC and DCIS combined – we have addressed this in sensitivity analyses. Estimates for ten-year overall incidence from our meta-regression models tended to have wide confidence intervals and should be interpreted with caution. Information on pathology review was provided by some of the included studies: several studies indicated lack of a centralised pathology review or review by breast-dedicated pathologists, and a few studies described review by several pathologists (details shown in Supplementary Table 4). Finally, almost all included studies were retrospective in nature.

5 Conclusions

Findings of this systematic review demonstrate moderate to high risk of BC development within ten years following initial diagnosis with a high-risk lesion, varying by lesion type. Future research assessing factors associated with variation in breast cancer risk would be useful among women with specific high-risk lesion types. This would further improve identification of women appropriate for enhanced prevention and screening strategies. Studies are also needed to evaluate screening outcomes associated with primary and supplemental screening strategies for women with high-risk lesions.

Funding

This work was supported by the 10.13039/501100001026 National Breast Cancer Foundation Chair in Breast Cancer Prevention grant (grant number EC-21-001 ) awarded to N.H. Author-specific funding includes: 10.13039/501100000925 NHMRC Investigator (Leader) grant (grant number 1194410 ) awarded to N.H.; 10.13039/100000054 National Cancer Institute at the National Institutes of Health (grant number R01CA282725 ) awarded to B.S.; 10.13039/501100001026 National Breast Cancer Foundation NBCF Investigator Initiated Research Scheme grant (grant number 2023/IIRS0028) awarded to M.L.M.

Ethical approval

Ethical approval was not required.

Data availability statement

All data are incorporated into the article and its online supplementary material.

CRediT authorship contribution statement

Jannah Baker: Writing – review & editing, Writing – original draft, Project administration, Methodology, Formal analysis, Data curation, Conceptualization. Naomi Noguchi: Writing – review & editing, Validation. M Luke Marinovich: Writing – review & editing, Validation, Methodology. Brian L. Sprague: Writing – review & editing. Elizabeth Salisbury: Writing – review & editing, Conceptualization. Nehmat Houssami: Writing – review & editing, Supervision, Methodology, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors have no conflicts of interest to declare.

Appendix A Supplementary data

The following is the Supplementary data to this article.Multimedia component 1

Multimedia component 1

Acknowledgements

The study sponsors had no role in the design of the study, the collection, analysis and interpretation of the data, the writing of the manuscript and the decision to submit the manuscript for publication.

Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.breast.2024.103807.
==== Refs
References

1 Sung H. Ferlay J. Siegel R.L. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin 71 3 2021 209 249 33538338
2 Heer E. Harper A. Escandor N. Global burden and trends in premenopausal and postmenopausal breast cancer: a population-based study Lancet Glob Health 8 8 2020 e1027 e1037 32710860
3 Cote M.L. Ruterbusch J.J. Alosh B. Benign breast disease and the risk of subsequent breast cancer in African American women Cancer Prev Res 5 12 2012 1375 1380
4 Hartmann L.C. Sellers T.A. Frost M.H. Benign breast disease and the risk of breast cancer N Engl J Med 353 3 2005 229 237 16034008
5 Castells X. Domingo L. Corominas J.M. Breast cancer risk after diagnosis by screening mammography of nonproliferative or proliferative benign breast disease: a study from a population-based screening program Breast Cancer Res Treat 149 1 2015 237 244 25503778
6 Kerlikowske K. Gard C.C. Tice J.A. Risk factors that increase risk of estrogen receptor-positive and -negative breast cancer J Natl Cancer Inst 109 5 2017 5
7 Page D.L. Kidd T.E. Jr. Dupont W.D. Simpson J.F. Rogers L.W. Lobular neoplasia of the breast: higher risk for subsequent invasive cancer predicted by more extensive disease Hum Pathol 22 12 1991 1232 1239 1748429
8 Adams A.L. Flat epithelial atypia: a review of current concepts Open Breast Cancer J 2 2010 90 94
9 Bombonati A. Sgroi D.C. The molecular pathology of breast cancer progression J Pathol 223 2 2011 307 317 21125683
10 Choi D.X. Eaton A.A. Olcese C. Blurry boundaries: do epithelial borderline lesions of the breast and ductal carcinoma in situ have similar rates of subsequent invasive cancer? Ann Surg Oncol 20 4 2013 1302 1310 23161115
11 Dyrstad S.W. Yan Y. Fowler A.M. Colditz G.A. Breast cancer risk associated with benign breast disease: systematic review and meta-analysis Breast Cancer Res Treat 149 3 2015 569 575 25636589
12 Calhoun B.C. Management of high-risk breast lesions: point-surveillance is a change in practice preceding evidence-based standardization AJR Am J Roentgenol 216 6 2021 1432 1433 33263420
13 Sharma N. Wilkinson L.S. Pinder S.E. The B3 conundrum-the radiologists' perspective Br J Radiol 90 1071 2017 20160595
14 Rubio I.T. Wyld L. Marotti L. European guidelines for the diagnosis, treatment and follow-up of breast lesions with uncertain malignant potential (B3 lesions) developed jointly by EUSOMA, EUSOBI, ESP (BWG) and ESSO Eur J Surg Oncol 50 1 2024 107292
15 Alvarado-Cabrero I. Valencia-Cedillo R. Estevez-Castro R. Preneoplasia of the breast and molecular landscape Arch Med Res 51 8 2020 845 850 32972772
16 Laws A. Leonard S. Hershey E. Upgrade rates and breast cancer development among germline pathogenic variant carriers with high-risk breast lesions Ann Surg Oncol 31 5 2024 3120 3127 38261128
17 Menes T.S. Kerlikowske K. Lange J. Subsequent breast cancer risk following diagnosis of atypical ductal hyperplasia on needle biopsy JAMA Oncol 3 1 2017 36 41 27607465
18 Baker J. Houssami N. Salisbury E. Marinovich L. Noguchi N. Atypical hyperplasia, lobular carcinoma in-situ, flat epithelial atypia and associated risk of developing breast cancer: National Institute for Health and Care Research [Available from: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=463941 2023
19 Wells G. Shea B. O'Connell D. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses 2021 The Ottawa Hospital [Available from: https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
20 CRAN-R project. rmeta: meta-Analysis [Available from: https://cran.r-project.org/web/packages/rmeta/index.html 2018
21 Page M.J. McKenzie J.E. Bossuyt P.M. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews Rev Esp Cardiol 74 9 2021 790 799 34446261
22 Acevedo F. Armengol V.D. Deng Z. Incidental atypical hyperplasia/LCIS in mammoplasty specimens and subsequent risk of breast cancer 2019 American Society of Clinical Oncology
23 Adams M.C. Falcon S. Mooney B.P. Short-term imaging follow-up of patients with concordant benign breast core needle biopsies: is it really worth it? Diagn Interv Radiol 20 6 2014 464 469 25205024
24 Arthur R. Wang Y. Ye K. Association between lifestyle, menstrual/reproductive history, and histological factors and risk of breast cancer in women biopsied for benign breast disease Breast Cancer Res Treat 165 3 2017 623 631 28643020
25 Ashbeck E.L. Rosenberg R.D. Stauber P.M. Key C.R. Benign breast biopsy diagnosis and subsequent risk of breast cancer Cancer Epidemiology Biomarkers and Prevention 16 3 2007 467 472
26 Aulmann S. Penzel R. Longerich T. Clonality of lobular carcinoma in situ (LCIS) and metachronous invasive breast cancer Breast Cancer Res Treat 107 3 2008 331 335 17380381
27 Bellini C. Nori Cucchiari J. Di Naro F. Breast lesions of uncertain malignant potential (B3) and the risk of breast cancer development: a long-term follow-up study Cancers 15 13 2023 3521 37444630
28 Boland P.A. Dunne E.C. Kovanaite A. Lobular intraepithelial neoplasia: outcomes and optimal management Breast J 26 12 2020 2383 2390 33270304
29 Boughey J.C. Hartmann L.C. Anderson S.S. Evaluation of the Tyrer-Cuzick (International Breast Cancer Intervention Study) model for breast cancer risk prediction in women with atypical hyperplasia J Clin Oncol 28 22 2010 3591 3596 20606088
30 Buckley E. Sullivan T. Farshid G. Hiller J. Roder D. Risk profile of breast cancer following atypical hyperplasia detected through organized screening Breast 24 3 2015 208 212 25681318
31 Byrne C. Schairer C. Brinton L.A. Effects of mammographic density and benign breast disease on breast cancer risk (United States) Cancer Causes Control 12 2 2001 103 110 11246838
32 Chun J. El-Tamer M. Joseph K.A. Ditkoff B.A. Schnabel F. Predictors of breast cancer development in a high-risk population Am J Surg 192 4 2006 474 477 16978952
33 Collins L.C. Aroner S.A. Connolly J.L. Breast cancer risk by extent and type of atypical hyperplasia: an update from the Nurses' Health Studies Cancer 122 4 2016 515 520 26565738
34 Coopey S.B. Mazzola E. Buckley J.M. The role of chemoprevention in modifying the risk of breast cancer in women with atypical breast lesions Breast Cancer Res Treat 136 3 2012 627 633 23117858
35 Degnim A.C. Dupont W.D. Radisky D.C. Extent of atypical hyperplasia stratifies breast cancer risk in 2 independent cohorts of women Cancer 122 19 2016 2971 2978 27352219
36 Donaldson A.R. McCarthy C. Goraya S. Breast cancer risk associated with atypical hyperplasia and lobular carcinoma in situ initially diagnosed on core-needle biopsy Cancer 124 3 2018 459 465 29023647
37 Dunne E.C. Quinn E.M. Stokes M. Upgrade rates and outcomes of screen-detected atypical intraductal epithelial proliferation (AIDEP) diagnosed on core needle biopsy Breast Dis 40 3 2021 155 160 33749633
38 Goldstein N.S. Kestin L.L. Vicini F.A. Clinicopathologic implications of E-cadherin reactivity in patients with lobular carcinoma in situ of the breast Cancer 92 4 2001 738 747 11550142
39 Goss P.E. Ingle J.N. Ales-Martinez J.E. Exemestane for breast-cancer prevention in postmenopausal women N Engl J Med 364 25 2011 2381 2391 21639806
40 Greene T. Tartter P.I. Smith S.R. Estabrook A. The significance of surgical margins for patients with atypical ductal hyperplasia Am J Surg 192 4 2006 499 501 16978959
41 Kabat G.C. Jones J.G. Olson N. A multi-center prospective cohort study of benign breast disease and risk of subsequent breast cancer Cancer Causes Control 21 6 2010 821 828 20084540
42 Karimi Z. Phillips J. Brook A. Upgrade rates of pure, radiology-pathology concordant lobular neoplasia diagnosed on breast core needle biopsy: is surgical excision warranted? Acad Radiol 29 7 2022 1029 1038 34702673
43 Kilgore L.J. Yi M. Bevers T. Risk of breast cancer in selected women with atypical ductal hyperplasia who do not undergo surgical excision Ann Surg 276 6 2022 e932 e936 33914469
44 Laws A. Katlin F. Nakhlis F. Atypical lobular hyperplasia and classic lobular carcinoma in situ can Be safely managed without surgical excision Ann Surg Oncol 29 3 2022 1660 1667 34554341
45 Levi F. Randimbison L. Te V.C. La Vecchia C. Invasive breast cancer following ductal and lobular carcinoma in situ of the breast Int J Cancer 116 5 2005 820 823 15838829
46 Lilleborge M. Falk R.S. Russnes H. Risk of breast cancer by prior screening results among women participating in BreastScreen Norway Cancer 125 19 2019 3330 3337 31206638
47 Lo L.L. Milne R.L. Liao Y. Validation of the IBIS breast cancer risk evaluator for women with lobular carcinoma in-situ Br J Cancer 119 1 2018 36 39 29925933
48 Louro J. Roman M. Posso M. Developing and validating an individualized breast cancer risk prediction model for women attending breast cancer screening PLoS One 16 3 2021 e0248930
49 Martel M. Barron-Rodriguez P. Tolgay Ocal I. Dotto J. Tavassoli F.A. Flat DIN 1 (flat epithelial atypia) on core needle biopsy: 63 cases identified retrospectively among 1,751 core biopsies performed over an 8-year period (1992-1999) Virchows Arch 451 5 2007 883 891 17786469
50 Mazzola E. Coopey S.B. Griffin M. Reassessing risk models for atypical hyperplasia: age may not matter Breast Cancer Res Treat 165 2 2017 285 291 28589368
51 Metovic J. Abate S.O. Borella F. The lobular neoplasia enigma: management and prognosis in a long follow-up case series World J Surg Oncol 19 1 2021 80 33736652
52 Middleton L.P. Sneige N. Coyne R. Most lobular carcinoma in situ and atypical lobular hyperplasia diagnosed on core needle biopsy can be managed clinically with radiologic follow-up in a multidisciplinary setting Cancer Med 3 3 2014 492 499 24639339
53 Miller K.N. Thomas S.M. Sergesketter A.R. The influence of body mass index on the histopathology and outcomes of patients diagnosed with atypical breast lesions Ann Surg Oncol 29 10 2022 6484 6494 35951136
54 Miller-Ocuin J.L. Fowler B.B. Coldren D.L. Is excisional biopsy needed for pure FEA diagnosed on a core biopsy? Am Surg 86 9 2020 1088 1090 32816560
55 Minami C.A. Zabor E.C. Gilbert E. Do body mass index and breast density impact cancer risk among women with lobular carcinoma in situ? Ann Surg Oncol 27 6 2020 1844 1851 31898097
56 Muller K.E. Roberts E. Zhao L. Jorns J.M. Isolated atypical lobular hyperplasia diagnosed on breast biopsy: low upgrade rate on subsequent excision with long-term follow-up Arch Pathol Lab Med 142 3 2018 391 395 29160721
57 Nagi C.S. O'Donnell J.E. Tismenetsky M. Bleiweiss I.J. Jaffer S.M. Lobular neoplasia on core needle biopsy does not require excision Cancer 112 10 2008 2152 2158 18348299
58 Nakhlis F. Harrison B.T. Giess C.S. Evaluating the rate of upgrade to invasive breast cancer and/or ductal carcinoma in situ following a core biopsy diagnosis of non-classic lobular carcinoma in situ Ann Surg Oncol 26 1 2019 55 61 30362065
59 Ouldamer L. Poisson E. Arbion F. All pure flat atypical atypia lesions of the breast diagnosed using percutaneous vacuum-assisted breast biopsy do not need surgical excision Breast 40 2018 4 9 29665448
60 Page D.L. Schuyler P.A. Dupont W.D. Atypical lobular hyperplasia as a unilateral predictor of breast cancer risk: a retrospective cohort study Lancet 361 9352 2003 125 129 12531579
61 Poola I. Yue Q. Gillespie J.W. Breast hyperplasias, risk signature, and breast cancer Cancer Prev Res 12 7 2019 471 480
62 Posso M. Alcantara R. Vazquez I. Mammographic features of benign breast lesions and risk of subsequent breast cancer in women attending breast cancer screening Eur Radiol 32 1 2022 621 629 34156554
63 Provencher L. Jacob S. Cote G. Low frequency of cancer occurrence in same breast quadrant diagnosed with lobular neoplasia at percutaneous needle biopsy Radiology 263 1 2012 43 52 22344406
64 Renshaw A.A. Gould E.W. Long term clinical follow-up of atypical ductal hyperplasia and lobular carcinoma in situ in breast core needle biopsies Pathology 48 1 2016 25 29 27020205
65 Said S.M. Visscher D.W. Nassar A. Flat epithelial atypia and risk of breast cancer: a Mayo cohort study Cancer 121 10 2015 1548 1555 25639678
66 Schiaffino S. Gristina L. Villa A. Flat epithelial atypia: conservative management of patients without residual microcalcifications post-vacuum-assisted breast biopsy Br J Radiol 91 1081 2018 20170484
67 Schiaffino S. Massone E. Gristina L. Vacuum assisted breast biopsy (VAB) excision of subcentimeter microcalcifications as an alternative to open biopsy for atypical ductal hyperplasia Br J Radiol 91 1085 2018 20180003
68 Sergesketter A.R. Thomas S.M. Fayanju O.M. The influence of age on the histopathology and prognosis of atypical breast lesions J Surg Res 241 2019 188 198 31028940
69 Shaaban A.M. Sloane J.P. West C.R. Histopathologic types of benign breast lesions and the risk of breast cancer: case-control study Am J Surg Pathol 26 4 2002 421 430 11914619
70 Singh K. Sung C.J. Quddus M.R. Descriptive study comparing outcomes of classic and nonclassic lobular carcinoma in situ (florid and pleomorphic) initially diagnosed on core needle biopsy Breast J 26 12 2020 2350 2356 33047861
71 Sohn V.Y. Arthurs Z.M. Kim F.S. Brown T.A. Lobular neoplasia: is surgical excision warranted? Am Surg 74 2 2008 172 177 18306873
72 Stefano M. Carla B.A. Giancarlo P. Underestimation rate of lobular intraepithelial neoplasia in vacuum-assisted breast biopsy Eur Radiol 24 7 2014 1651 1658 24744196
73 Susnik B. Day D. Abeln E. Surgical outcomes of lobular neoplasia diagnosed in core biopsy: prospective study of 316 cases Clin Breast Cancer 16 6 2016 507 513 27425222
74 Akashi-Tanaka S. Fukutomi T. Nanasawa T. Treatment of noninvasive carcinoma: fifteen-year results at the national cancer center hospital in tokyo Breast Cancer 7 4 2000 341 344 11114862
75 Tice J.A. O'Meara E.S. Weaver D.L. Benign breast disease, mammographic breast density, and the risk of breast cancer J Natl Cancer Inst 105 14 2013 1043 1049 23744877
76 Tice J.A. Miglioretti D.L. Li C.S. Breast density and benign breast disease: risk assessment to identify women at high risk of breast cancer J Clin Oncol 33 28 2015 3137 3143 26282663
77 To T. Wall C. Baines C.J. Miller A.B. Is carcinoma in situ a precursor lesion of invasive breast cancer? Int J Cancer 135 7 2014 1646 1652 24615647
78 van Maaren M.C. Avila A.O. van Manen J.G. Trends in incidence, treatment, survival and subsequent breast cancer in lobular carcinoma in situ in The Netherlands: a population-based analysis Breast 59 2021 376 382 34428722
79 Visscher D.W. Frost M.H. Hartmann L.C. Clinicopathologic features of breast cancers that develop in women with previous benign breast disease Cancer 122 3 2016 378 385 26512815
80 Whiffen A. El-Tamer M. Taback B. Feldman S. Joseph K.A. Predictors of breast cancer development in women with atypical ductal hyperplasia and atypical lobular hyperplasia Ann Surg Oncol 18 2 2011 463 467 20878246
81 Wong S.M. King T. Boileau J.F. Barry W.T. Golshan M. Population-based analysis of breast cancer incidence and survival outcomes in women diagnosed with lobular carcinoma in situ Ann Surg Oncol 24 9 2017 2509 2517 28455673
82 Worsham M.J. Abrams J. Raju U. Breast cancer incidence in a cohort of women with benign breast disease from a multiethnic, primary health care population Breast J 13 2 2007 115 121 17319851
83 Worsham M.J. Raju U. Lu M. Risk factors for breast cancer from benign breast disease in a diverse population Breast Cancer Res Treat 118 1 2009 1 7 18836828
84 Yoon J.H. Koo J.S. Lee H.S. Factors predicting breast cancer development in women during surveillance after surgery for atypical ductal hyperplasia of the breast: analysis of clinical, radiologic, and histopathologic features Ann Surg Oncol 27 10 2020 3614 3622 32314161
85 Zarwan C. Diamond O. Lam P. Longitudinal study of breast cancer risk markers Breast J 27 1 2021 48 51 33099843
86 Bevers T.B. Niell B.L. Baker J.L. NCCN guidelines(R) insights: breast cancer screening and diagnosis, version 1.2023 J Natl Compr Canc Netw 21 9 2023 900 909 37673117
