Abstract
INTRODUCTION:
Atypical intraductal epithelial proliferation (AIDEP) is a breast lesion categorised as “indeterminate” if identified on core needle biopsy (CNB). The rate at which these lesions are upgraded following diagnostic excision varies in the literature. Women diagnosed with AIDEP are thought to be at increased risk of breast cancer. Our aim was to identify the rate of upgrade to invasive or in situ carcinoma in a group of patients diagnosed with AIDEP on screening mammography and to quantify their risk of subsequent breast cancer.
METHODS:
We conducted a retrospective review of a prospectively maintained database containing all patients diagnosed with AIDEP on CNB between 2005 and 2012 in an Irish breast screening centre. Basic demographic data was collected along with details of the original CNB result, rate of upgrade to carcinoma and details of any subsequent cancer diagnoses.
RESULTS:
In total 113 patients were diagnosed with AIDEP on CNB during the study period. The upgrade rate on diagnostic excision was 28.3% (n = 32). 6.2% (n = 7) were upgraded to invasive cancer and 22.1% (n = 25) to DCIS. 81 patients were not upgraded on diagnostic excision and were offered 5 years of annual mammographic surveillance. 9.88% (8/81) of these patients went on to receive a subsequent diagnosis of malignancy. The mean time to diagnosis of these subsequent cancers was 65.41 months (range 20.18–145.21).
CONCLUSION:
Our data showing an upgrade rate of 28% to carcinoma reflects recently published data and we believe it supports the continued practice of excising AIDEP to exclude co-existing carcinoma.
Introduction
While breast screening has been proven to save lives [1], concern relating to the over-diagnosis and over-treatment of screening populations is a common cause for debate [2–4]. With the advent of breast screening and improvements in imaging technology there has been a significant increase in the frequency with which we diagnose patients with breast lesions of uncertain malignant potential (B3) [5].
The system of classification of breast lesions favoured in Europe classifies normal breast tissue as “B1” and scales up to a description of “B5” for biopsies demonstrating unequivocal malignancy. Between these two extremes lie lesions of uncertain malignant potential, or B3 lesions. A broad array of histological subtypes are included in this subgroup, including atypical intraductal epithelial proliferation (AIDEP), non-pleomorphic lobular neoplasia (LN), flat epithelial atypia (FEA) and radial scar. Each histological subtype has its own distinct features and risk of upgrade to invasive or in situ carcinoma [6]. In the most recent NHS position paper on the management of B3 lesions Pinder et al. define AIDEP as a specific small lesion (microfocal, <2 mm in extent) composed of a uniform, small cell, atypical epithelial proliferation either admixed with a non-uniform process, such as usual epithelial hyperplasia, and/or is too small for diagnosis of low-grade DCIS [7].
Current standard of practice in Ireland is to offer diagnostic excision or vacuum assisted excision to all patients diagnosed with AIDEP on core needle biopsy (CNB) to exclude the presence of carcinoma. The reported risk of upgrade of these lesions is variable. A recent meta-analysis reported an upgrade rate of 32% with a 95% confidence interval of 24–31% [8]. However previous studies have reported a wide range of upgrade rates, from as low as 8% up to 87% [9,10].
These lesions are also thought to confer an increased risk of developing a subsequent breast cancer [11], therefore all patients with findings of atypia on diagnostic excision enter surveillance with annual mammography for 5 years post excision.
The aim of this study was to investigate the rate of upgrade from screen-detected AIDEP on core needle biopsy (CNB) to invasive or in-situ carcinoma and to determine the risk of subsequent development of breast cancer.
Methods
We conducted a retrospective review of a prospectively maintained database of all B3 lesions identified on CNB in an Irish breast screening centre between 2005 and 2012 and selected out those with a histological diagnosis of AIDEP.
All patients diagnosed with a B3 lesion on CNB were discussed at a specialised multidisciplinary meeting (MDM) with breast radiologists, breast surgeons and breast pathologists in attendance. Standard of care was to offer diagnostic excision to all those patients diagnosed with a B3 lesion. Any patients with a finding of atypia on CNB or diagnostic excision underwent surveillance with annual mammography for 5 years post operatively.
Data collected included patient demographics, BI-RADS score, clinical examination findings and the presence or absence of calcifications. We also collected data on the original biopsy histology and the subsequent resection histology along with information about the patients’ follow up and any subsequent diagnosis of breast cancer they may have received.
We excluded patients who were diagnosed with a concurrent malignancy at the time of the B3 result as well as those who failed to proceed to diagnostic excision and those with incomplete data.
The terminology used to describe the various subtypes of B3 lesions is variable, we used the most up to date NHS breast screening guidelines to standardise our descriptors [7].
Results
451 patients were diagnosed with a B3 lesion during the study period (2005–2012). 6 of these patients were found to have a synchronous breast malignancy at the time of their B3 diagnosis, 17 had incomplete data and 3 did not proceed to diagnostic excision. These 26 patients were therefore excluded. This left 425 eligible for inclusion. AIDEP was diagnosed on CNB in 113 cases (26.59%).
35 (30.97%) patients with AIDEP were diagnosed at the age of their first screening mammogram (50/51) and the mean age at diagnosis was 54.5 years (range 50–64).
The upgrade rate on diagnostic excision was 28.3% (n = 32). 6.2% (n = 7) were upgraded to invasive cancer and 22.1% (n = 25) to DCIS.
Amongst the 32 patients upgraded on diagnostic excision 23 (5 with invasive disease and 18 with in situ carcinoma) proceeded to have curative surgery and follow-up at our institution. The remainder received treatment at other institutions.
Of the 5 patients upgraded to invasive carcinoma 20% (n = 1) were found to have grade 1 disease, with the remaining 80% (n = 4) having grade 2. The mean tumour size was 0.7 cm (range 0.2–1.9 cm). All were oestrogen receptor (ER) positive, 80% were progesterone receptor (PR) positive and one (20%) overexpressed HER2. Breast conserving surgery was performed in 60% (n = 3) of cases and all of these patients proceeded to undergo adjuvant radiotherapy. All patients underwent a sentinel lymph node biopsy and in all cases this was negative for metastatic disease. Following MDT discussion 40% (n = 2) were offered adjuvant chemotherapy. Just one patient was diagnosed with further disease during follow-up; this patient was diagnosed with DCIS 62 months following the original diagnosis (Table 1).
Summary of characteristics of patients upgraded to invasive carcinoma on diagnostic excision
Summary of characteristics of patients upgraded to invasive carcinoma on diagnostic excision
Among those 25 patients upgraded to ductal carcinoma in situ (DCIS) on diagnostic excision, 18 proceeded to have therapeutic surgery in our institution. The mean extent of disease was 15.8 mm (range 6–25 mm). 94.4% (n = 17) underwent breast conserving surgery and subsequent radiotherapy with just one patient (5.6%) requiring mastectomy. One patient (5.6%) went on to have a subsequent diagnosis of DCIS at 16 months post diagnosis (Table 2).
Summary of characteristics of patients upgraded to DCIS on diagnostic excision
83 patients were not upgraded following diagnostic excision, of these 45 (53.08%, 43/81) had findings of atypia on diagnostic excision. In 37 cases this further atypia was due to a finding of ADH on their resection specimen, in the remaining cases the finding of atypia was as a result of ALH (6 cases) or an atypical fibroepithelial lesion (2 cases). In the remaining 36 cases without upgrade resection specimens were classified as benign, the final histological findings on diagnostic excision in these cases included; epithelial proliferation without atypia in 15 cases, radial scar in 8 cases, fibroepithelial lesion in 6, papilloma in 2 and adenosis in 5.
81 patients were not upgraded on diagnostic excision and were offered 5 years of annual mammographic surveillance. 12.35% (10/81) of these patients had no follow-up mammogram and whilst the majority of patients did undergo some form of follow-up just 22.22% (18/81) completed five years of annual mammography in line with local guidelines. 9.88% (8/81) of these patients went on to receive a subsequent diagnosis of malignancy. 3.7% (3/81) were diagnosed with DCIS and 6.17% (5/81) were found to have an invasive cancer. The mean time to diagnosis of these subsequent cancers was 65.41 months (range 20.18–145.21) and 50% (4/8) of the subsequent cancers were diagnosed outside of the standard 5 years of annual mammography. In most of these cases of subsequent cancer (62.5%, 5/8) their original diagnostic excision specimens had demonstrated a finding of ADH. In the remaining 3 cases one patient had a finding on diagnostic excision which was consistent with ALH, one had a radial scar without atypia and one had a fibroepithelial lesion without significant atypical features.
Summary of available data reporting the rate of upgrade of AIDEP to carcinoma
Improvements in the accuracy of mammographic screening have led to an increase in the identification of AIDEP on CNB. Standard practice internationally is to proceed with either diagnostic excision or excisional biopsy, due to the risk of upgrade to carcinoma on final pathology [7]. Upgrade rates vary widely in the literature. Although women with a diagnosis on AIDEP are thought to have an increased risk of subsequent breast cancer [5], there is controversy regarding optimal follow-up and management. We report upgrade rates and outcomes of screening detected AIDEP in a single Irish screening centre.
In our cohort of patients with screen detected AIDEP, the upgrade rate to invasive or in situ carcinoma was 28.3% (32/113). In those patients upgraded to invasive carcinoma, all were low to intermediate grade, all were found to have ER positive, lymph node negative disease and the majority had T1 disease (11/18, 61.1%).
The rate of upgrade to carcinoma in our cohort is comparable to that reported elsewhere. Variability in the histological reporting and classification of these lesions means that comparison of published data can be challenging (the UK and Ireland favours the use of the term AIDEP to describe these lesions when diagnosed on CNB, but the terminology used in the literature is inconsistent). In 2018 Richter-Ehrenstein et al. [12] reported their rate of upgrade as high as 40%. However, other groups such as EL-Sayed [13] and Dillon [14] have reported lower upgrade rates of 32% and 26%, respectively. A recent systematic review and meta-analysis [8] reported an overall upgrade rate of 28%, with individual included studies reporting upgrade rates ranging from 2% to 62%. (See Table 3 for summary of reported upgrade rates) The upgrade rate of 28% demonstrated in this study justifies the current practice of diagnostic or vacuum assisted excision of these lesions.
Previous studies have attempted to identify predictors of increased risk of upgrade and hence reduce the need for diagnostic excision. Multiple independent risk factors for upgrade have been demonstrated, including size of tissue sample, presence of palpable abnormality on clinical examination, age over 50 at diagnosis [15–18]. However, there remains no well recognised or reliable way to predict upgrade. Farshid et al. [15], studied 114 cases of ADH diagnosed over a ten-year period in a screening centre. Their study was limited by the low numbers included but proposed that increasing size of the index screen detected lesion as an independent predictor of upgrade. Gumus [16] et al. examined 150 cases of ADH over an eleven-year period, they did not account for whether these cases were screening detected or symptomatic. They identified increasing lesion size, increasing degree of radiologist suspicion (R score) and smaller tissue sample size as independent risk factors for upgrade. Khoury [18] et al. proposed a normogram to predict risk of upgrade preoperatively. In the study of 203 consecutive cases of ADH diagnosed between 2006 and 2013 to aid in the development in of this measure the only variable that reached significance in predicting upgrade was size of disease focus.
Given concerns regarding overtreatment, coupled with the fact that increasing the volume of tissue at diagnostic biopsy has been shown to decrease upgrade risk [15–18] the advent of vacuum assisted excision (VAE) has heralded a welcome alternative to operative intervention in the management of high risk breast lesions [19]. The opportunity to increase tissue yield using minimally invasive means has been welcomed by patients and clinicians alike; some 90% of patients preferred VAE to excisional biopsy, both in terms of the cosmetic result and physical/mental stress involved [20,21], the most recent NHS breast screening guidelines [22] recommend VAE as an equal alternative to diagnostic excision in AIDEP and most other B3 lesions (excluding papillomas with atypia, cellular fibroepithelial lesion and other rarer subtypes such as spindle cell lesions). Our study details practice in the years prior to the introduction of VAE in our institution.
Women with a diagnosis of AIDEP are thought to have an increased risk of future development of breast cancer. Hartmann et al. reported that the incidence of in situ and invasive cancer following diagnosis of ADH was 29% over a period of 25 years [23] and Menes found that risk of breast cancer was 2.6 higher in patients with a diagnosis of ADH than in the general population over 10 years post diagnosis [24]. However, conversely, Merker et al. reported no subsequent diagnosis of carcinoma during 5 years of annual mammogram and just one case over a ten year period (1/130, 0.77%) [25], although just 34% of their cohort completed a full 5 years of annual mammographic surveillance and as such there may have been further cases which were lost to follow-up. In Ireland, women diagnosed with AIDEP are currently offered 5 years of annual mammographic surveillance before returning to routine screening. Current standard of practice in many units in the UK is also to offer 5 years of annual mammogram surveillance post diagnostic excision after which the patient returns to the national screening service. However, the most recent NHS Breast Screening Program guidelines [22] published in 2016 do not give recommendations on the provision of post-operative surveillance given the paucity and quality of available data. In our study, 9.88% (8/81) of patients not upgraded on diagnostic excision went on to be diagnosed with a subsequent malignancy during follow-up. The mean time to diagnosis of these subsequent cancers was 65.4 months. Just 42.9% (n = 3) of these subsequent cancers were diagnosed during the traditional 5 years of annual mammography. Therefore, the majority of those patients who received a subsequent diagnosis of carcinoma did so as symptomatic patients outside of the five-year recommended window (57%, 4/7). This suggests that a diagnosis of AIDEP on CNB is not associated with short-term increased risk of breast cancer, but rather an increased lifetime risk.
Although it has yet to become standard of care in the UK and Ireland, the efficacy of chemoprevention in high risk patients, including those with AIDEP, has been well established [26,27]. DeCensi reported randomised controlled data demonstrating halving of the rate of recurrence of intraepithelial breast neoplasia with use of low dose Tamoxifen [26]. There is conflicting evidence with regards to whether chemoprophylaxis leads to an increased risk of thrombotic events but following consideration of the available evidence the American Society of Clinical Oncology have recommended considering chemoprophylaxis in those women at an increased risk of developing breast cancer [28]. Despite the available evidence studies show that only a small number of at risk patients will opt for chemoprophylaxis when it is offered [27]. Shared decision making around preventative strategies such as chemoprophylaxis presents a communication challenge, it may be that the well reported side effect and risk profile of endocrine therapies such as tamoxifen are not agreeable to our population in a prophylactic setting [27].
Our study is limited by the fact that many of our patients did not complete five years of annual mammography; 12.35% (10/81) of patients not upgraded to in-situ/invasive carcinoma had no follow-up mammogram. Only 22.22% (18/81) completed five years of annual mammography in line with local guidelines. Many of the patients who went on to develop a subsequent malignancy post diagnostic excision presented through symptomatic rather than surveillance pathways, meaning that it is conceivable that some members of the original cohort did go on to have subsequent diagnoses managed by other services.
Conclusion
Our data showing an upgrade rate of 28% to carcinoma supports the ongoing routine excision of AIDEP. Our findings suggest that women with a diagnosis of AIDEP on CNB are at increased risk of developing breast cancer, and that most of these cancers occur outside the standard 5 years of annual surveillance, suggesting that increased lifelong surveillance may be warranted. Further research is needed to clarify the most appropriate management of these patients.
Conflict of interest
There is no conflict of interest to declare.