ABSTRACT BACKGROUND The diagnosis, management and prognosis of microinvasive breast carcinoma remain controversial. METHODS We analysed the outcomes of patients with DCIS with and without

microinvasion diagnosed between 2003 and 2012 within the Sloane project. RESULTS Microinvasion was recorded in 521 of 11,285 patients (4.6%), with considerable variation in reported

incidence among screening units (0–25%). Microinvasion was associated with high-grade DCIS, larger DCIS size, comedo necrosis and solid, cribriform architecture (all _P_ _<_ 0.001).

Microinvasion was more frequent in patients who underwent mastectomy compared with breast-conserving surgery (BCS) (6.9% vs 3.6%, _P_ _<_  0.001), and in those undergoing axillary nodal

subsequent ipsilateral invasion was of Grade 3 in 71.4% of patients with microinvasion vs 30.4% in DCIS without microinvasion (_P_ = 0.02). Distant metastasis and breast cancer mortality

were higher with microinvasion compared with DCIS only (1.2% vs 0.3%, _P_ = 0.01 and 2.1% vs 0.8%; _P_ = 0.005). CONCLUSIONS The higher breast cancer mortality with microinvasion indicates a

more aggressive disease. SIMILAR CONTENT BEING VIEWED BY OTHERS MICROINVASIVE BREAST CANCER AND THE ROLE OF SENTINEL LYMPH NODE BIOPSY Article Open access 20 July 2022 PATHOLOGICAL FEATURES

OF 11,337 PATIENTS WITH PRIMARY DUCTAL CARCINOMA IN SITU (DCIS) AND SUBSEQUENT EVENTS: RESULTS FROM THE UK SLOANE PROJECT Article Open access 17 November 2020 INVASIVE RECURRENCE AFTER

BREAST CONSERVING TREATMENT OF DUCTAL CARCINOMA IN SITU OF THE BREAST IN THE NETHERLANDS: TIME TRENDS AND THE ASSOCIATION WITH TUMOUR GRADE Article 09 July 2024 INTRODUCTION Microinvasion,

defined as one or more foci of invasion of ≤1 mm in size, is predominantly identified in association with high-grade ductal carcinoma in situ (DCIS). However, it can also be seen with other

DCIS grades, lobular carcinoma in situ (LCIS) and Paget’s disease [1]. In 1995, microinvasion was categorised by the UK National Coordinating Committee for Breast Pathology as a focus of

invasion 1 mm or less identified within the non-specialised stroma. Based on this criterion, small foci of invasion measuring less than 1 mm but localised to the specialised loose stroma

within lobules were not interpreted as microinvasion. This stromal feature was subsequently dropped from the histological definition, partly because of the subsequent uncertainty of how to

classify lesions within the specialised stroma (if not as microinvasion) and partly due to the difficulty in distinguishing specialised from non-specialised stroma, especially in the context

of high-grade DCIS that is often associated with dense chronic inflammation [2]. The accurate incidence of microinvasion is difficult to ascertain, but it is estimated that it can be seen

in ~5–10% of DCIS cases and comprises around 1% of all breast cancers [3]. The Surveillance, Epidemiology and End Results (SEER) registry data reported microinvasion in 3.2% out of a total

of 134,569 women registered [4]. Controversy also exists as to the natural history of microinvasive disease and its impact on outcomes. Whether microinvasion behaves, and should be managed,

as DCIS or whether it represents true, albeit small, invasive disease is debated. Moreover, there is no consensus as to whether there is a role for routine axillary staging if a diagnosis of

microinvasion has been made. For example, one group has recommended lymph-node sampling in patients with DCIS with microinvasion, but this was based on a series of 51 DCIS patients of whom

only 6 had microinvasion; 5 had nodal involvement, including 3 patients from the microinvasion group [5]. There are, however, no specific national or international guidelines on whether or

not axillary lymph-node examination should be performed in patients with microinvasion, reflecting the paucity of data. Large, well-annotated cohorts with long-term follow-up are therefore

needed to address these clinically relevant issues. Following our report of the pathological features of pure DCIS [6, 7], we aimed to analyse the natural history, management and outcome of

DCIS with microinvasive carcinoma diagnosed by either preoperative core biopsy or at surgical excision within the UK Sloane Project, a prospective cohort of screen-detected non-invasive

breast cancer with long-term follow-up. METHODS The Sloane Project is a UK prospective cohort study of screen-detected non-invasive breast neoplasia governed by NHS England and NHS

Improvement (previously Public Health England, PHE). DCIS lesions, including those with microinvasion, diagnosed between 2003 and 2012 were submitted from UK NHS Breast Screening Programme

Units. Comprehensive imaging, surgical, pathology and oncology data were collected at screening unit and hospital levels and submitted to the Sloane Project team, who entered information

into a secure database. All participating units followed the Sloane Project protocols [8] and the National Health Service Breast Screening Programme (NHSBSP) guidelines for pathology

reporting, including DCIS cytonuclear grading, definitions of atypia, microinvasion, comedo necrosis and assessment of surgical margins [2]. Pathologists were also required to participate in

the National Breast External Quality Assurance Scheme. Follow-up data, including subsequent events occurring 6 months or more from the initial diagnosis, and patient survival were collected

from local data and cross-referenced against national registries to ensure accuracy [6, 9]. For patient outcome data from England, the following national datasets were cross-checked:

English Cancer Analysis System (CAS), Hospital Episode Statistics (HES), Cancer Waiting Times (CWT), English National Radiotherapy Dataset (RTDS), Systemic Anti-Cancer Therapy dataset

(SACT), Office for National Statistics (ONS) mortality data, Mortality and Birth Information System (MBIS). The methodology of the Sloane project data collection and verification is

described in detail elsewhere (Clements et al., manuscript submitted). RESULTS Of a total of 11,285 DCIS cases included, microinvasion was identified in 512 (4.6%). There was no significant

difference in the incidence of microinvasion by patient age; 4.7% and 4.6% of patients under and over the age of 50, respectively, had microinvasion recorded, with an incidence of 4.2% and

4.9% of patients under and over the age of 60, respectively. The reported incidence of microinvasion decreased from 7% in 2003/2004 to 3% in 2011/2012 with an overall incidence over the

study period of 5% (Table 1). However, marked variation in the reported incidence of microinvasion in those patients submitted to the Project was noted amongst contributing screening units

(0–25%). CLINICOPATHOLOGICAL FEATURES ASSOCIATED WITH MICROINVASION Microinvasion was significantly associated with high cytonuclear grade of DCIS; it was reported in 5.9% of 7182 cases of

high-grade DCIS compared to 2.9% of 3093 intermediate grade and <1% of 995 low-grade DCIS (_P_ < 0.001). Microinvasion was associated with larger DCIS lesions (_P_ < 0.001) being

diagnosed in 2.2% of DCIS less than 10 mm in size, 3.9% of DCIS 10–20 mm, 5.8% of DCIS 20–30 mm, 5.2% of DCIS 30–40 mm and 8.0% of DCIS > 40 mm. It was also associated with the presence

of comedo necrosis (_P_ < 0.001), and solid (_P_ < 0.001), cribriform (_P_ < 0.001) or flat (_P_ = 0.03) DCIS architectures (Table 2). SURGERY AND ADJUVANT THERAPY Microinvasion was

identified more frequently in patients who underwent mastectomy (6.9%) compared with those who had breast-conserving surgery (BCS) (3.6%; _P_ < 0.001). In patients who underwent BCS,

there was no significant association between the presence of microinvasion and margin status or margin width (Table 2). Axillary surgery was performed in 3406 patients (Table 2). This

included sentinel lymph node (SLN) in 1533 patients, SLN and sampling (_n_ = 170), axillary node sampling (_n_ = 1570), SLNB and clearance (ANC, _n_ = 11) and ANC (_n_ = 114). The latter

(ANC) group was mainly patients who underwent mastectomy (_n_ = 103). The percentage of ANC and mastectomy in the microinvasion patients declined from 7.9% at the start of the project in

2003/2004 to 1.4% in 2011/2012. Unfortunately, data on whether the diagnosis of microinvasion was made on core biopsy or subsequent excision is not available; therefore, it was not possible

to ascertain the proportion of patients who underwent nodal surgery at the first operation as a result of a preoperative diagnosis of microinvasion. However, axillary nodal surgery was more

commonly performed in patients diagnosed with DCIS with microinvasion compared to those without (60.4% compared to 30.3%). This remained the case when the analysis was restricted to patients

who underwent BCS. In patients who had BCS as the initial surgery, axillary node surgery was more frequently performed as subsequent surgery in patients with microinvasive carcinoma (38.4%

for microinvasion vs 7.9% for DCIS alone, _P_ < 0.001) (Table 3). The rate of nodal metastasis at first nodal surgery was, however, very low and not statistically significantly different

between those with and without microinvasion (2/521, 0.4% and 10/10764, 0.1%, respectively, _P_ = 0.27). Patients with microinvasion who underwent BCS were more likely to receive

radiotherapy than those with BCS for pure DCIS (_P_ < 0.001) (Table 2). SUBSEQUENT EVENTS Follow-up data were available for patients from England only (_n_ = 9423). These patients were

followed up for a maximum of 164 months with a median of 110 months (range 4–164 months). Patients with pure DCIS and those with DCIS plus microinvasion showed a very low event rate with no

statistically significant difference between the groups. Of the patients diagnosed with microinvasion and treated by BCS, 6 of 261 (3%) had ipsilateral recurrent DCIS and 11 of 261 (4.2%)

developed ipsilateral invasive carcinoma. The corresponding proportions of ipsilateral DCIS recurrence and ipsilateral invasive disease for those with pure (i.e., without microinvasion) were

3.4% (211 of 6262) and 5.6% (349 of 6262), respectively, _P_ = 0.39. All subsequent ipsilateral DCIS recurrences following a primary diagnosis of high-grade DCIS with microinvasion were

high grade compared with 102/118 (86.4%) of recurrences following high-grade DCIS without microinvasion (_P_ = 0.43). All subsequent contralateral DCIS recurrences (6/6) following a primary

diagnosis of DCIS with microinvasion were high-grade compared with 24/39 (61.5%) of recurrences following high-grade DCIS without microinvasion (_P_ = 0.06). Furthermore, the majority

(71.4%) of the subsequent invasive carcinomas in the same breast were of histological grade 3. For patients with DCIS without microinvasion at initial diagnosis, only 30.4% of the

ipsilateral subsequent invasive carcinomas were grade 3 (_P_ = 0.02). Interestingly, all contralateral DCIS developing following an initial diagnosis of DCIS with microinvasion were also of

high grade compared with 59.3% in patients with DCIS only (_P_ = 0.03). Lesion size was not associated with the frequency of subsequent events in the patients with microinvasion. Of note, in

those with DCIS without microinvasion, there were more subsequent events in those with lesions under 2 cm compared with those above 2 cm (_P_ = 0.005), possibly reflecting the effect of

adjuvant therapy more frequently administered for larger lesions. Ipsilateral events were similar in frequency in patients with and without microinvasion who underwent BCS, _P_ = 0.68 (Table

 4). DISTANT METASTASES The overall distant metastasis rate was very low (0.4%), with only 46 patients with distant metastases identified. Analysis of these low numbers revealed

statistically significantly more frequent distant metastases in those patients with DCIS with microinvasion (6/511, 1.2%) compared to those with pure DCIS (40/10764, 0.3%), _P_ = 0.01.

PATIENT SURVIVAL Follow-up data were available for patients in England (_n_ = 9423). Breast cancer-specific mortality was higher (2.1%) in patients with microinvasion compared with those

without it (0.8%). This difference was statistically significant (_P_ = 0.005) (Fig. 1a). Patients who presented with subsequent distant metastasis following an original diagnosis of DCIS

plus microinvasion had worse overall survival compared with those with distant metastasis but with initial presentation of DCIS only, Log-rank test, _P_ = 0.02 (Fig. 1b). All-cause mortality

was not, however, statistically significantly different between patients presenting with and without microinvasive carcinoma, Log-rank test, _P_ = 0.94 (Fig. 1c). The original DCIS lesion

size had no effect on survival. When the size was dichotomised using a cut-off value of 2 cm, there was no significant relation between tumour size and patient survival in those with pure

DCIS and in patients with microinvasion (log-rank _P_ value 0.55 and 0.59, respectively). This persisted when the analysis was limited to high-grade DCIS only (_P_ = 0.5 and 0.71,

respectively). DISCUSSION We report here on 11,285 patients with screen-detected DCIS specifically examining the features, management and outcome of those 521 with associated microinvasion.

The subsequent event rate remained low for both pure DCIS and DCIS with microinvasion; however, the presence of microinvasion was associated with a significantly poorer breast

cancer-specific mortality compared to that of patients with DCIS lesions without microinvasion. Moreover, patients with subsequent distant metastases who had an initial diagnosis of DCIS and

microinvasive carcinoma had poorer survival than those without microinvasion suggesting that DCIS with microinvasive carcinoma behaves like an invasive cancer with a more aggressive

behaviour than pure DCIS. The largest study to date on microinvasive carcinoma showed similar effects on mortality. A SEER data analysis [10] of 161,394 women with pure DCIS and 13,489 with

DCIS and microinvasion reported that the 20-year breast cancer-specific mortality rates were 3.8% and 6.9%, respectively. The rate associated with microinvasion was similar to that of small

invasive carcinoma of up to 1 cm (6.8%) and lower than that for women with invasive carcinoma of 1.1–2.0 cm in size (12.1%). However, another, meta-analysis of axillary staging in patients

with DCIS and microinvasion, that included 2959 patients from 23 studies, showed a survival rate of patients with microinvasion was overall very similar to those with pure DCIS [11]. In a

smaller Chinese cohort, of 359 pure DCIS lesions and 80 DCIS with microinvasion and 31 months of follow-up, Fang et al. reported that those with microinvasion had 3-year disease-free

survival (DFS), similar to stage pT1a invasive carcinoma and poorer than pure DCIS but there was no significant difference in the overall survival between the three groups [12]. In another

small Singaporean study of 198 DCIS cases, of which only 12 showed microinvasion, Chen et al reported that those patients with DCIS with microinvasion had a statistically significant worse

outcome, including shorter recurrence free survival (_P_ = 0.01), which persisted on multivariate Cox regression analysis. Those lesions exhibited significantly higher densities of tumour

microenvironment cellular infiltrate including CD4, FOXP3, CD163 and PDL-1, potentially indicating a role for the inflammatory immune response in disease progression [13]. In the current

cohort, axillary sampling was more frequently performed in the presence of microinvasion (in either preoperative core biopsy or found at surgical excision). It is unfortunate that it is not

known if this was a result of microinvasion being identified on preoperative core biopsy or because, for example, the patient presented with large, high-grade DCIS. A meta-analysis of

axillary staging in patients with DCIS with microinvasion by Choi et al. reported a 2% rate of nodal macrometastasis, with rates for micrometastases and isolated tumour cell clusters (ITCs)

of 2% and 3%. There were significant differences in the likelihood of macrometastasis according to focality of microinvasion (whether focal, focal and multifocal, or multifocal) showed

significant differences for macrometastases (_P_ = 0.033), but this was not the case for micrometastases or ITCs. The authors concluded that, as axillary staging in microinvasion is unlikely

to change patient management, a multidisciplinary approach is preferable to routine axillary staging [11]. The number of microinvasive foci has been shown to be prognostic in other series.

In a study of 229 examples of pure DCIS and 264 cases of DCIS with microinvasion (median follow-up of 3.9 years), 0 and 13 showed nodal metastasis, respectively. Lesions with three or more

microinvasive foci were significantly associated with nodal positivity (_P_ = 0.03) and disease relapse (_P_ = 0.05). The relapse-free survival for DCIS with microinvasion and for DCIS only

was 95.4% and 99%, respectively [14]. A recent study, of 359 microinvasive carcinomas, showed that the number of microinvasive foci and HER2 positivity indicated a more aggressive disease

and suggested that those patients might benefit from systemic therapy [15]. Similar to invasive carcinoma, the presence of multiple microinvasive foci should be stated in the pathology

reports, however, their precise number is not currently a mandatory parameter for assessment and recording in the DCIS pathology reporting guidelines [2, 16, 17]. The number of microinvasive

foci in any one DCIS lesion was not recorded within the Sloane data, and central pathology review of Sloane histology sections was not performed. We cannot therefore examine the

significance of this feature in the current cohort. Nodal metastasis has been reported to be more frequent in larger DCIS lesions. In one study of 24 patients with DCIS measuring 25 mm or

more, microinvasion was identified in 25% of cases. The incidence of microinvasion, invasive carcinoma and nodal metastasis following the diagnosis of DCIS was directly related to tumour

size, and the authors recommended axillary node sampling for DCIS lesions measuring 35 mm or more [18]. In the current large series, microinvasion was associated with larger DCIS size but we

found no association between DCIS size and contemporaneous nodal metastasis, or recurrence or patient mortality in patients with microinvasion. Microscopic examination remains the gold

standard for diagnosing microinvasion although a few imaging studies have attempted to provide some radiological pointers to the presence of microinvasion. Comparing the imaging features of

94 patients with DCIS and 53 patients with DCIS plus microinvasion, Wang et al. [19] reported that large areas of calcifications and distortion on mammography and/or calcification and

increased vascularity on ultrasound were radiologically suggestive of microinvasion. Most of the published data in the literature is based on a definitive diagnosis of microinvasion

diagnosed on surgical excision. Indeed, some would argue that a definitive diagnosis of microinvasive carcinoma cannot be made on a core biopsy, as one cannot be certain that the very small

invasive focus in the core is not the edge of a (much) larger invasive lesion. The Memorial Sloan–Kettering Cancer Center published their experience with suspected (_n_ = 105) and definite

microinvasive cases (_n_ = 264) diagnosed on conventional needle core biopsies over a 10-year period (2007–2017) [20]. Lesions were upgraded to true invasion (i.e., >1 mm) on surgical

excision in 28% and 35% of cases, respectively. Axillary staging at initial surgery was performed in 77% and 94%, respectively (_P_ < 0.001). In the whole cohort when axillary staging was

performed, factors predictive of the pN1 stage included young age and large areas of microcalcification (_P_ < 0.001 for both). On multivariate analysis, the presence of definite

microinvasion in core biopsy significantly increased the risk of nodal metastasis (CI = 1.01–60.7, _P_ = 0.04). The rate of nodal metastasis with suspected microinvasion in a core biopsy was

very low (<1%) and similar to pure DCIS [20]. From a practical point of view, when very small foci of invasive disease are identified, either in core biopsy samples or surgical excision,

further levels are extremely helpful to assess the histology, as the invasive focus may be larger on deeper levels, or foci may join up and thus be categorised as true invasive carcinoma.

Conversely, it may be clearer that the focus is actually cancerisation of lobules (or of a sclerosing lesion) rather than true invasion. A panel of immunohistochemistry for myoepithelial

markers can be helpful to confirm invasion, while noting that the myoepithelial layer around DCIS, with or without microinvasion, can be discontinuous/attenuated. However, when multiple

small foci of invasion are seen, one of the pathological challenges is the lack of guidance on whether foci that are close together should be added to represent one single (invasive) tumour

or multiple microinvasive foci. In this context, deeper levels can again be valuable to assess if the foci join up or increase in size. While most pure DCIS lesions are hormone

receptor-positive, lesions with microinvasion are reportedly more often ER negative and HER2-positive. In a study of 289 DCIS lesions that included 88 with microinvasion, Liu et al. reported

the latter to be associated with larger DCIS size, high cytonuclear grade and increased ki67 proliferation index [21]. In our referral opinion experience, we have seen examples of missed

foci of microinvasion in surgical specimens followed by recurrent HER2-positive invasive carcinoma with associated nodal metastasis. This highlights the importance of a thorough histological

examination of high-grade DCIS to identify both microinvasion and true invasive disease. ER, PR and HER2 immunohistochemistry, however, is not performed routinely in the UK on DCIS cases as

per the NHSBSP breast reporting guidelines and therefore information on receptor status of DCIS/microinvasion within the Sloane Project was only available for a minority of cases. However,

the current practice is evolving, and pathologists are increasingly reporting ER/PR/HER2 on microinvasive foci as additional useful data that could guide adjuvant therapy and provide

prognostic information. The lack of consistency in the histological definition of microinvasion, particularly in the early literature may explain, at least in part, the conflicting

conclusions of various studies. Lagios et al. [22] defined microinvasion as small invasive foci measuring less than 1 mm in 1982, but the term was subsequently used inconsistently, with a

broad range of definitions. In 1988, Silver and Tavassoli [23] defined a microinvasive lesion as DCIS with a single focus of invasion not exceeding 2 mm in the largest dimension, or up to

three foci of invasion, none of which was more than 1 mm in the greatest dimension. The former group clearly included lesions that would currently be classified as small (pT1a) invasive

carcinoma. The current strict definition and updated and clarified histological guidelines are likely to be the reasons for the reduction in the incidence of microinvasion noted over the

past decade in the Breast Screening Programme Sloane data. The diagnostic criteria for the current Sloane cohort (2003–2012) included an invasive size of <1 mm within non-specialised

stroma. The latter criterion was removed in the UK 2016 guidelines, in line with international guidance; in view of the difficulties in discerning non-specialised stroma within high-grade

DCIS where the brisk inflammatory infiltrate is likely to obscure the stromal features. This update post-dated the Sloane inclusion period and therefore should not have impacted on the

diagnostic criteria of the included lesions. As for multifocality, current pathology guidelines recommend measurement of the largest focus if multiple microinvasive foci are identified

microscopically, not adding them up, with a comment on the number/multiplicity of foci of microinvasion [16] The reason for variation in the reported incidence among screening units is,

however, not clear and requires further evaluation. It is unlikely to be true due to demographic differences and raises concern about a lack of reproducibility in the pathological diagnosis.

Due to the focal nature of the lesion, the consistency of pathologists reporting of microinvasion has not been evaluated in previous studies, or in the UK Breast External Quality Assurance

Scheme. The recent transition of the scheme to digital whole slide images will enable assessment of the consistency of reporting of focal lesions such as microinvasive carcinoma and will be

valuable as an educational tool. Superimposed on the current standard definition (foci of invasion of ≤1 mm in size), de Mascarel et al. have proposed sub-classifying microinvasion in the

periductal stroma into M1 (invasive individual cells) and M2 lesions (invasive small clusters). The authors reported no nodal metastasis in patients in the M1 group whereas 10.1% of patients

in the M2 group had nodal metastasis [24]. They suggested that there were two biological types of microinvasion, one (M1) behaving like DCIS and another (M2) with a greater capacity for

invasive behaviour. This clearly has potential clinical relevance but requires further validation. Molecular signatures that distinguish poor prognosis DCIS that is likely to progress to

invasive carcinoma/metastasise are being investigated, and recent genomic data from the Sloane cohort highlighted clonal similarities between the primary DCIS and the subsequent invasive

recurrences in 75% of cases [25]. Going forward, the molecular profile may provide an attractive companion to standard histopathological examination to dissect the good prognosis

microinvasive lesions from those that have the potential to frankly invade/metastasise. To summarise, this is the second largest series of microinvasion reported to date, and the largest

prospective well-characterised cohort of screen-detected DCIS and microinvasion globally. The main strengths of the study include the large cohort size, prospective nature of data collection

and robustness and rigorous validation of the collected multidisciplinary data, making the results valid and generalisable. Some of the limitations of this study include the lack of

information on the number of microinvasive foci and whether the diagnosis of microinvasion was made on core biopsy and/or surgical excision; although we anticipate that the majority will

have been diagnosed on surgical excision specimens. The Sloane audit was a prospective audit that collected a huge amount of high-quality pathology, surgical, oncology and outcome data, but

central pathology review was not required. Based on these findings, however, microinvasive breast carcinoma appears to be more aggressive than pure DCIS and is associated with higher rate of

distant metastases and higher breast cancer mortality. It is also of note that subsequent invasive carcinoma recurrences were mostly Grade 3 and thus of poorer prognostic histology. We

believe that a sentinel node biopsy should be considered, in a multidisciplinary approach, with appropriate discussion with patients, if the diagnosis of very small foci of invasion, akin to

microinvasion, is made on core biopsy. There is no evidence, as yet, to suggest whether such patients benefit from subsequent systemic therapy. Several factors such as the number of

microinvasive foci, the molecular profile specially HER2 status and possibly the genomic signature may need to be collectively considered by the multidisciplinary team and patients to tailor

subsequent therapy. DATA AVAILABILITY Data are held by NHS England and NHS Improvement (formerly 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 the breast screening research advisory committee (RAC) and NHS England and NHS Improvement. Data will subsequently

only be released by NHS England and NHS Improvement to researchers under the approval and in an anonymised or depersonalised format, with a data sharing contract in place. REFERENCES * The

WHO Classification of Tumours Editorial Board. WHO Classification of tumours—breast tumours, 5th Edition. Lyon: International Agency for Research On Cancer (IARC); 2019. * Guidelines Working

Group of the UK National Coordinating Committee for Breast Pathology. Pathology reporting of breast disease in surgical excision specimens incorporating the dataset for histological

reporting of breast cancer. https://www.rcpath.org/profession/guidelines/cancer-datasets-and-tissue-pathways.html. Accessed 1 September 2022. The Royal College of Pathologists; 2016. *

Adamovich TL, Simmons RM. Ductal carcinoma in situ with microinvasion. Am J Surg. 2003;186:112–6. https://doi.org/10.1016/s0002-9610(03)00166-1. Article  Google Scholar  * Champion CD, Ren

Y, Thomas SM, Fayanju OM, Rosenberger LH, Greenup RA, et al. DCIS with microinvasion: is it in situ or invasive disease? Ann surgical Oncol. 2019;26:3124–32.

https://doi.org/10.1245/s10434-019-07556-9. Article  Google Scholar  * van la Parra RF, Ernst MF, Barneveld PC, Broekman JM, Rutten MJ, Bosscha K. The value of sentinel lymph node biopsy in

ductal carcinoma in situ (DCIS) and DCIS with microinvasion of the breast. Eur J Surgical Oncol: J Eur Soc Surgical Oncol Br Assoc Surgical Oncol. 2008;34:631–5.

https://doi.org/10.1016/j.ejso.2007.08.003. Article  Google Scholar  * Shaaban AM, Hilton B, Clements K, Provenzano E, Cheung S, Wallis MG, et al. Pathological features of 11,337 patients

with primary ductal carcinoma in situ (DCIS) and subsequent events: results from the UK Sloane Project. Br J Cancer. 2021;124:1009–17. https://doi.org/10.1038/s41416-020-01152-5. Article 

CAS  Google Scholar  * Shaaban AM, Hilton B, Clements K, Pinder SE, Thompson AM. Reply to “comment on: pathological features of 11,337 patients with primary ductal carcinoma in situ (DCIS)

and subsequent events: results from the UK Sloane Project”. Br J Cancer. 2021;124:1463–4. https://doi.org/10.1038/s41416-021-01281-5. Article  Google Scholar  * The National Archives.

https://webarchive.nationalarchives.gov.uk/20180903111938/http://www.sloaneproject.co.uk/Pathology.htm * Thompson AM, Clements K, Cheung S, Pinder SE, Lawrence G, Sawyer E, et al. Management

and 5-year outcomes in 9938 women with screen-detected ductal carcinoma in situ: the UK Sloane Project. Eur J Cancer. 2018;101:210–9. https://doi.org/10.1016/j.ejca.2018.06.027. Article 

Google Scholar  * Sopik V, Sun P, Narod SA. Impact of microinvasion on breast cancer mortality in women with ductal carcinoma in situ. Breast Cancer Res Treat. 2018;167:787–95.

https://doi.org/10.1007/s10549-017-4572-2. Article  Google Scholar  * Choi B, Jegatheeswaran L, Nakhoul M, Haria P, Srivastava R, Karki S, et al. Axillary staging in ductal carcinoma in situ

with microinvasion: a meta-analysis. Surg Oncol. 2021;37:101557. https://doi.org/10.1016/j.suronc.2021.101557. Article  Google Scholar  * Fang Y, Wu J, Wang W, Fei X, Zong Y, Chen X, et al.

Biologic behavior and long-term outcomes of breast ductal carcinoma in situ with microinvasion. Oncotarget. 2016;7:64182–90. https://doi.org/10.18632/oncotarget.11639. Article  Google

Scholar  * Chen XY, Thike AA, Koh VCY, Nasir NDM, Bay BH, Tan PH. Breast ductal carcinoma in situ associated with microinvasion induces immunological response and predicts ipsilateral

invasive recurrence. Virchows Arch: Int J Pathol. 2021;478:679–86. https://doi.org/10.1007/s00428-020-02959-6. Article  CAS  Google Scholar  * Zhang G, Li C, Tian G, Cheng X, Li Y, Ma L.

Comparison of breast ductal carcinoma in situ and ductal carcinoma in situ with microinvasion, and analysis of axillary lymph node metastasis. Medicine. 2020;99:e23593.

https://doi.org/10.1097/MD.0000000000023593. Article  CAS  Google Scholar  * Si J, Guo R, Pan H, Lu X, Guo Z, Han C, et al. Multiple microinvasion foci in ductal carcinoma in situ is

associated with an increased risk of recurrence and worse survival outcome. Front Oncol. 2020;10:607502. https://doi.org/10.3389/fonc.2020.607502. Article  Google Scholar  * Fox S, Chen CJ,

Chua B, Collins LC, Foschini MP, Mann B, et al. Ductal carcinoma in situ, variants of lobular carcinoma in situ and low grade lesions histopathology reporting guide. International

Collaboration on Cancer Reporting: Sydney, Australia; 2021. * Fox SB, Webster F, Chen CJ, Chua B, Collins L, Foschini MP, et al. Dataset for pathology reporting of ductal carcinoma in situ,

variants of lobular carcinoma in situ and low-grade lesions: recommendations from the International Collaboration on Cancer Reporting (ICCR). Histopathology. 2022; e-pub ahead of print 24

July 2022; https://doi.org/10.1111/his.14725. * Maffuz A, Barroso-Bravo S, Najera I, Zarco G, Alvarado-Cabrero I, Rodriguez-Cuevas SA. Tumor size as predictor of microinvasion, invasion, and

axillary metastasis in ductal carcinoma in situ. J Exp Clin Cancer Res. 2006;25:223–7. CAS  Google Scholar  * Wang H, Lin J, Lai J, Tan C, Yang Y, Gu R, et al. Imaging features that

distinguish pure ductal carcinoma in situ (DCIS) from DCIS with microinvasion. Mol Clin Oncol. 2019;11:313–9. https://doi.org/10.3892/mco.2019.1891. Article  CAS  Google Scholar  * Flanagan

MR, Stempel M, Brogi E, Morrow M, Cody HS 3rd. Is sentinel lymph node biopsy required for a core biopsy diagnosis of ductal carcinoma in situ with microinvasion? Ann surgical Oncol.

2019;26:2738–46. https://doi.org/10.1245/s10434-019-07475-9. Article  Google Scholar  * Liu BT, Ding JN, Wang JL, Li ZS, Ding YL, Ma R. Differences in pathologic characteristics between

ductal carcinoma in situ (DCIS), DCIS with microinvasion and DCIS with invasive ductal carcinoma. Int J Clin Exp Pathol. 2020;13:1066–72. CAS  Google Scholar  * Lagios MD, Westdahl PR,

Margolin FR, Rose MR. Duct carcinoma in situ. Relationship of extent of noninvasive disease to the frequency of occult invasion, multicentricity, lymph node metastases, and short-term

treatment failures. Cancer. 1982;50:1309–14. https://doi.org/10.1002/1097-0142(19821001)50. Article  CAS  Google Scholar  * Silver SA, Tavassoli FA. Mammary ductal carcinoma in situ with

microinvasion. Cancer. 1998;82:2382–90. Article  CAS  Google Scholar  * de Mascarel I, MacGrogan G, Mathoulin-Pelissier S, Soubeyran I, Picot V, Coindre JM. Breast ductal carcinoma in situ

with microinvasion: a definition supported by a long-term study of 1248 serially sectioned ductal carcinomas. Cancer. 2002;94:2134–42. https://doi.org/10.1002/cncr.10451. Article  Google

Scholar  * Lips EH, Kumar T, Megalios A, Visser LL, Sheinman M, Fortunato A, et al. Genomic analysis defines clonal relationships of ductal carcinoma in situ and recurrent invasive breast

cancer. Nat Genet. 2022;54:850–60. https://doi.org/10.1038/s41588-022-01082-3. Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS This work uses data provided by patients and

collected by the UK NHSBSP as part of their care and support. We thank all patients and all breast units who have participated in the Sloane Project Audit. This work was presented as a

poster (Number: P3-12-36) at the San Antonio Breast Cancer Symposium 2021 and the abstract published in _Cancer Research Suppl_, 2021. “The diagnosis and prognosis of ductal carcinoma in

situ (DCIS) with microinvasion - Results from the United Kingdom Sloane project Shaaban AM, Hilton B, Clements K, Dodwell D, Sharma N, Kirwan C, Sawyer E, Maxwell A, Wallis M, Stobart H,

Mylvaganam S, Litherland J, Brace-McDonnell S, Dulson-Cox J, Kearins O, Provenzano E, Pinder S, Thompson A”. This work was presented as an oral presentation at the British Breast Group

Meeting 2021 and was awarded the Forrest prize for best presentation. “What do we know about ductal carcinoma in situ (DCIS) with microinvasion? Data from the UK Sloane Project. Abeer M

Shaaban, Bridget Hilton, Karen Clements, David Dodwell, Nisha Sharma, Cliona Kirwan, Elinor Sawyer, Anthony Maxwell, Matthew Wallis, Hilary Stobart, Senthurun Mylvaganam, Janet Litherland,

Samantha Brace-McDonnell, Joanne Dulson-Cox, Olive Kearins, Elena Provenzano, Sarah E Pinder, Alastair M Thompson.” FUNDING 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 Clements, E Sawyer, AM Thompson and SE Pinder. AMS is supported by the Birmingham

CRUK Centre grant (C17422/A25154). This research/work was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not

necessarily those of the NIHR or the Department of Health and Social Care. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Queen Elizabeth Hospital Birmingham and University of Birmingham,

Birmingham, UK Abeer M. Shaaban * NHS England and NHS Improvement, Birmingham, UK Bridget Hilton, Karen Clements, Joanne Dulson-Cox & Olive Kearins * Nuffield Department of Population

Health, University of Oxford, Oxford, UK David Dodwell * Leeds Teaching Hospitals NHS Trust, Leeds, UK Nisha Sharma * Division of Informatics, Imaging & Data Sciences. School of Health

Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK Cliona Kirwan & Anthony Maxwell * School of Cancer and Pharmaceutical Sciences,

King’s College London, Guy’s Comprehensive Cancer Centre at Guy’s and St Thomas’ Hospitals NHS Foundation Trust, London, UK Elinor Sawyer & Sarah E. Pinder * Addenbrookes Hospital,

Cambridge and Cambridge Breast Unit, and NIHR Cambridge Biomedical Research Centre, Cambridge University Hospitals NHS Trust, Cambridge, UK Matthew Wallis & Elena Provenzano *

Independent Cancer Patients’ Voice, London, UK Hilary Stobart & Samantha Brace-McDonnell * Royal Wolverhampton Hospital NHS Trust, Wolverhampton, UK Senthurun Mylvaganam * NHS Greater

Glasgow and Clyde, Glasgow, UK Janet Litherland * Nottingham University Hospitals, Nottingham, UK Ian O. Ellis * Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells,

School of Medicine, Nottingham City Hospital, The University of Nottingham, Nottingham, UK Ian O. Ellis * Baylor College of Medicine, Houston, TX, USA Alastair M. Thompson Authors * Abeer M.

Shaaban View author publications You can also search for this author inPubMed Google Scholar * Bridget Hilton View author publications You can also search for this author inPubMed Google

Scholar * Karen Clements View author publications You can also search for this author inPubMed Google Scholar * David Dodwell View author publications You can also search for this author

inPubMed Google Scholar * Nisha Sharma View author publications You can also search for this author inPubMed Google Scholar * Cliona Kirwan View author publications You can also search for

this author inPubMed Google Scholar * Elinor Sawyer View author publications You can also search for this author inPubMed Google Scholar * Anthony Maxwell View author publications You can

also search for this author inPubMed Google Scholar * Matthew Wallis View author publications You can also search for this author inPubMed Google Scholar * Hilary Stobart View author

publications You can also search for this author inPubMed Google Scholar * Senthurun Mylvaganam View author publications You can also search for this author inPubMed Google Scholar * Janet

Litherland View author publications You can also search for this author inPubMed Google Scholar * Samantha Brace-McDonnell View author publications You can also search for this author

inPubMed Google Scholar * Joanne Dulson-Cox View author publications You can also search for this author inPubMed Google Scholar * Olive Kearins View author publications You can also search

for this author inPubMed Google Scholar * Elena Provenzano View author publications You can also search for this author inPubMed Google Scholar * Ian O. Ellis View author publications You

can also search for this author inPubMed Google Scholar * Sarah E. Pinder View author publications You can also search for this author inPubMed Google Scholar * Alastair M. Thompson View

author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS BH, KC, SC and OK: data collection and statistical analysis. AMS: data interpretation, reviewed

the literature, produced the first draft of the manuscript. SP and AMT: data interpretation, writing the manuscript, oversaw the project. EP: data interpretation, contributed to writing the

manuscript. DD, NS, CK, ES, AM, MW, HS, SM, JL, SBM, JC-CEP, AMH, JT, MGW and IOE: data interpretation, input into writing up and appraisal of the manuscript. All authors approved the final

version of the manuscript. CORRESPONDING AUTHOR Correspondence to Abeer M. Shaaban. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. 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. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. SUPPLEMENTARY

INFORMATION AJ-CHECKLIST RIGHTS AND PERMISSIONS OPEN ACCESS This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation,

distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and

indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to

the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will

need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Reprints and permissions ABOUT THIS ARTICLE

CITE THIS ARTICLE Shaaban, A.M., Hilton, B., Clements, K. _et al._ The presentation, management and outcome of patients with ductal carcinoma in situ (DCIS) with microinvasion (invasion ≤1 

mm in size)—results from the UK Sloane Project. _Br J Cancer_ 127, 2125–2132 (2022). https://doi.org/10.1038/s41416-022-01983-4 Download citation * Received: 26 March 2022 * Revised: 30

August 2022 * Accepted: 05 September 2022 * Published: 12 October 2022 * Issue Date: 07 December 2022 * DOI: https://doi.org/10.1038/s41416-022-01983-4 SHARE THIS ARTICLE Anyone you share

the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer

Nature SharedIt content-sharing initiative