Abstract
Background/Aim: We conducted this single-center, retrospective study to identify predictors of upgrading to malignancy and to discuss the necessity of additional excision biopsy in patients who were diagnosed with atypical ductal hyperplasia (ADH) at ultrasound (US)-guided vacuum-assisted breast biopsy (VABB) based on our 18-year, single-center experience. Patients and Methods: The current study was conducted in a total of 12,160 patients who were evaluated at our medical institution during an 18-year period between January of 2003 and December of 2020. We included the patients who were diagnosed with ADH at US-guided VABB using the Mammotome® (Devicor Medical Products, Inc., Cincinnati, OH, USA). We therefore included a total of 114 patients (n=114) with ADH in the current study. Results: Of 114 eligible patients, 36 underwent additional excision biopsy and the remaining 78 did not. Of these 36 patients, 15 were found to have an upgrading to malignancy at a rate of upgrading of 41.7%. These include 7 cases (46.6%) of low-grade ductal carcinoma in situ (DCIS), 3 cases (20.0%) of intermediate grade DCIS, 1 case (6.7%) of microinvasive DCIS, 3 cases (20.0%) of multifocal lobular carcinoma in situ, and 1 case (6.7%) of mucinous carcinoma. Finally, only suspicious microcalcification on mammography was a significant predictor of upgrading to malignancy (p=0.023). Conclusion: An additional excision biopsy is recommended to reduce the rate of upgrading to malignancy in patients who were diagnosed with ADH through a US-guided VABB.
A benign proliferative breast lesion, atypical ductal hyperplasia (ADH) is histopathologically characterized by proliferation of monomorphic, evenly distributed epithelial cells in the terminal ductal-lobular unit. Moreover, although ADH resembles low-grade ductal carcinoma in situ (DCIS), the former can be differentially diagnosed from the latter based on an admixed population of non-monomorphic cells or the involvement of <2 duct spaces or an area of <2 mm in diameter (1, 2). It is known that patients with ADH have a 4- to 5-fold highe risk of developing breast cancer (BC) (3, 4).
In an effort to further evaluate suspicious lesions seen on breast ultrasound (US) or mammography (MMG), US-guided core needle biopsy (CNB), US-guided vacuum-assisted biopsy (VABB), and stereotactic-guided VABB are widely used (5, 6). A diagnosis of ADH can be made based on percutaneous biopsy of the breast tissue. Due to the limited amount of tissue sample collected using a standard CNB, however, a correct diagnosis of it poses a challenge for surgeons (1). Decision on excision biopsy of the lesion can be justified based on the fact that DCIS or invasive BC may occur at an incidence of 30-54% in patients who were diagnosed with ADH at CNB (2, 7). Presumably, this may arise from sampling error, for which the rate of underestimation can be calculated and is estimated at 7-65% (8, 9). However, VABB is advantageous in obtaining a greater amount of tissue sample; it provides a lower rate of underestimation, ranging from 9% to 36% (10, 11).
The rate of underestimation may be raised in association with diverse factors; these include breast symptoms, MMG findings other than microcalcification alone, the calibre of biopsy needle, the number of biopsy samples, the concurrent presence of intraductal papilloma, the existence of atypia, the level of a pathologist’s skill, a patient’s age of >60 years old, a family history of BC or a patient’s past history of BC (8, 12, 13). There is no doubt as to the recommendation of additional excision biopsy to patients who were diagnosed with ADH at CNB. Still, however, there are no established criteria for recommending additional excision biopsy to patients who were diagnosed with ADH at VABB (10, 14, 15).
Given the above background, we conducted this retrospective study to identify predictors of upgrading to malignancy and to discuss the necessity of additional excision biopsy in patients who were diagnosed with ADH at US-guided VABB based on our 18-year, single-center experience.
Patients and Methods
Study patients and setting. The current single-center, retrospective study was conducted in a total of 12,160 patients (15,808 lesions) who were evaluated at our medical institution during an 18-year period between January of 2003 and December of 2020.
Inclusion criteria for the current study were as follows:
1) Patients who were diagnosed with ADH at US-guided VABB using the Mammotome® (Devicor Medical Products, Inc., Cincinnati, OH, USA)
2) Patients with available medical records.
Exclusion criteria for the current study were as follows:
1) Patients with no available medical records.
2) Patients who were deemed to be ineligible for study participation according to our judgment.
We therefore included a total of 114 patients (n=114) with ADH in the current study. The study was approved by the Institutional Review Board (IRB) of our medical institution (IRB approval #: GCI 17-35). Informed consent was waived due to its retrospective nature.
US-guided VABB protocol. US-guided VABB was performed based on the Breast Imaging Reporting and Data System (BI-RADS) lexicon of the American College of Radiology (ACR) category, as previously described (6). In detail, a complete excision of the BI-RADS category 3 or 4A lesion of ≤3.5 cm in size was achieved using an 8-G needle. However, an incision biopsy of the BI-RADS category 4B-5 lesion was achieved. Patients with the BI-RADS category 3 lesion were routinely followed up using US at a 6-month interval. During the follow-up period, they were also further evaluated using US-guided VABB when the long and short axis of the lesion were increased by ≥3 mm or the shape of lesion was upgraded to ≥4A. Other criteria for performing US-guided VABB of the BI-RADS category 3 lesion include unavailability of follow-up due to regional locations, pregnancy or plan for augmentation mammaplasty, great concerns for palpable lesions, a past history of receiving BC surgery in the ipsilateral breast, a family or patient history of BC, those whose results of previous fine-needle aspiration biopsy (FNAB) or CNB are unclear or those with a confirmed diagnosis of the BI-RADS B3 lesion (e.g., papillary neoplasm, ADH, phyllodes tumor or mucinous lesions).
Excluding the patients undergoing augmentation mammaplasty, an 8-G needle was used to perform a biopsy of the lesion measuring as ≤3.5 cm. An incision was made on the skin at a length of 3-5 mm at an operating room under local anesthesia by a single board-certified specialist in surgery. This maneuver was performed until a complete excision of the lesion was confirmed on US. The length of procedure time was defined as that extending from the start of identifying the target lesion using US to the exit of Mammotome® probe from the breast and the initiation of hemostasis.
Patient evaluation and criteria. We performed a retrospective analysis of the patients’ medical records. The rate of upgrading to malignancy was calculated by dividing the number of malignancy-proven lesions by the total number of lesions. In the 78 patients who did not undergo additional excision biopsy, however, the upgrading to malignancy was not determined when there were no imaging findings that were suggestive of malignancy during the follow-up period.
Statistical analysis of the data. Data were analyzed using the IBM SPSS Statistics for Windows, Version 21.0 (Released 2012; IBM Corp., Armonk, NY, USA). To determine the statistical significance of differences, χ2-test, χ2 for trend, and Fisher’s exact test were used, as indicated. Statistical significance was set at p<0.05.
Results
Baseline characteristics of the patients. Of a total of 114 patients who were diagnosed with ADH using a US-guided VABB, 36 underwent additional excision biopsy and the remaining 78 did not. Disposition of the study patients is shown in Figure 1. In these 36 patients, a follow-up was performed using US at a 6-month interval and MMG at a 1-year interval during a median follow-up period of 40 months (range=24-199 months). Baseline characteristics of the patients are represented in Table I.
Study flow chart.
Age distribution of the patients with atypical ductal hyperplasia who underwent additional excision biopsy (n=36).
Following an analysis of the size of the lesion, 30.6% of total cases had a size of 0.6-1.0 cm, being the most prevalent. Most of the lesions had a size of ≤3 cm. Overall, the size of the lesion was 1.65 cm. Moreover, it was 1.77 cm in the upgraded group and 1.59 cm in the non-upgraded group. This difference reached no statistical significance (Table II).
Size of the lesion of the patients with atypical ductal hyperplasia who underwent additional excision biopsy (n=36).
On physical examination, the proportion of the palpable lesion amounted to 8.3%; most of the lesions (92.7%) were found to be non-palpable. According to the BI-RADS category, the proportions of the category 3, 4a and 4b lesions were 50.0%, 47.2% and 2.8%, respectively. There was no significant difference in the rate of upgrading to malignancy depending on the BI-RADS category (Table III and Table IV).
Characteristics of the lesion (n=36).
Histopathologic results of malignant lesions (n=15).
Upgrading to malignancy. Of the 36 patients who were diagnosed with ADH and underwent additional excision biopsy, 15 were found to have an upgrading to malignancy at a rate of upgrading of 41.7%. These included 7 cases (46.6%) of low-grade DCIS, 3 cases (20.0%) of intermediate grade DCIS, 1 case (6.7%) of microinvasive DCIS, 3 cases (20.0%) of multifocal lobular carcinoma in situ (LCIS), and 1 case (6.7%) of mucinous carcinoma. This showed that carcinoma in situ accounted for most cases of ADH (93.3%) (Table IV).
Predictors of upgrading to malignancy. To identify potential predictors of upgrading to malignancy, various factors, such as age, the size of the lesion, BI-RADS category, concurrent presence of columnar cell lesion, number of foci, palpability and suspicious microcalcification on MMG, were analyzed. This showed that only suspicious microcalcification on MMG was a significant predictor of upgrading to malignancy (p=0.023) (Table V).
Clinical characteristics of the patients (n=36).
Discussion
In clinical practice, the underestimation of malignancy of a lesion harvested using a CNB or a VABB remains problematic. In detail, it is a main issue whether and if ever how additional excision biopsy should be performed to avoid underestimation in patients who were diagnosed with ADH through a percutaneous biopsy (16–18). To date, many studies have been therefore conducted to examine whether additional excision biopsy is needed for such patients, although no consensus has been reached (19, 20). The underestimation of malignancy is closely associated with two factors: the similarity with ADH and the relatively smaller amount of tissue sample. A pathologist may therefore miss a diagnosis of DCIS while it is actually present in patients with ADH. Moreover, some cases of ADH are characterized by a concurrent presence of DCIS or invasive carcinoma (8). By definition, the upgrading to malignancy is referred to as an initial diagnosis of ADH accompanied by DCIS or invasive carcinoma at additional excisional surgery. It has been estimated at 4-54% according to a review of the literature (8). It would therefore be reasonable to propose additional excision to patients who are diagnosed with ADH.
In our series, we achieved a complete excision of the lesion using a US-guided VABB but found a relatively higher rate of upgrading to malignancy (41.7%). This is in agreement with previous published studies (7). Taken together, we assume that patients with ADH are in need of additional excision to lower the rate of upgrading to malignancy.
On the other hand, there are also some previous studies describing factors associated with a decreased rate of upgrading to malignancy in patients with ADH. Recently, Peña et al. reported that all the patients who were diagnosed with ADH through a percutaneous biopsy cannot be upgraded despite additional excision biopsy. According to these authors, if treated, such patients would be burdened with a high cost of overtreatment (21). Peña et al. additionally suggested other factors associated with a decreased rate of upgrading to malignancy (4.9%); these include a lack of individual cell necrosis from the core sample collected through a percutaneous biopsy, the localization of the lesion to 1 focus despite a more than 50% removal of the target lesion, and the presence of the lesion even in 2-3 foci after the removal of ≥90% of the sample. Patients who met these criteria were classified as a low-risk group; they could be followed up without undergoing additional excision biopsy (21).
In addition, Verschuur-Maes et al. performed a systematic review of the previous published studies and showed that the possibility of underestimation reached 20% in cases in which columnar cell lesions (CCL) were concurrently present with ADH in the sample collected through a CNB. Thus, these authors mentioned the importance of a concurrent presence of CCL as a factor that is closely associated with additional excision biopsy (22).
Ko et al. reported that a rate of upgrading to malignancy of ≤2% would lead to an imaging-based follow-up in patients who were diagnosed with ADH through a CNB. Moreover, these authors also analyzed factors that are associated with a rate of upgrading to malignancy of ≥2%, thus showing that such factors include palpable lesions, microcalcification on MMG, the size of lesion measuring as ≥15 mm on US, and the age at the time of diagnosis of ADH of ≥50 years old as independent predictors of upgrading to malignancy. According to these authors, however, focal ADH was a negative predictor of it (23).
According to a review of the previous literature about factors that are associated with additional excision biopsy in patients who were diagnosed with ADH through a CNB or VABB, the size of the lesion, number of foci, radiological features, needle type, association with calcification, residual presence of the lesion, and individual cell necrosis have been suggested as predictors of it. Of these, multifocality with more than 2 foci of ADH on CNB or VABB and associated individual cell necrosis had a significant positive correlation with upgrading to malignancy (2, 7, 24–26). In our series, however, only suspicious microcalcification on MMG was found to be a significant predictor of upgrading to malignancy (p=0.023). These results are not slightly in agreement with several previous studies. We classified the number of foci into 1, 2-3, and >3 to analyze the rate of upgrading to malignancy in our series, although we found no statistical significance in its difference depending on the number of foci. These results are not in agreement with a previous study conducted by Wagoner et al., according to whom the rate of upgrading to malignancy was 7%, 13%, and 72% when the number of foci was 1-2, 3, and ≥4, respectively. These authors also noted that the scope of the lesion had a significant positive correlation with the rate of upgrading to malignancy (27).
According to McGhan et al., age of <50 years old, focal atypia, and a lack of residual calcifications are factors that are associated with a lower rate of underestimation in a total of 114 patients who were diagnosed with ADH through a CNB undergoing additional excision biopsy (11). From similar contexts, it has also been reported that additional excision biopsy would not be needed for patients with ADH in whom small-sized lesions are restricted to three foci (28). As shown in the current study, however, the rate of upgrading to malignancy was 42.9%, 40%, and 33.3% when the number of ADH foci was 1, 2-3, and >3, respectively. It can therefore be inferred that surgical excision might be helpful for lowering the rate of upgrading to malignancy even in patients with a size of lesion of ≤1 cm and ADH localized to 1 focus.
In the current study, we achieved a complete excision of the lesion through an 8-G VABB, although we found a rate of upgrading to malignancy of 41.7%, a relatively higher value. This suggests that additional excision biopsy might be an essential modality for lowering the rate of upgrading to malignancy.
As reported by Rageth et al. in the second International Consensus Conference on B3 lesions, open excision (OE) is recommended for patients who were diagnosed with ADH through a VABB despite a complete excision of the lesion. These authors also reported that OE should be considered only in patients with older age. In addition, they also added that patients with ADH undergoing additional excision biopsy would be in need of continuous follow-up monitoring possibly because such patients might be at increased risks of malignancy in the distant areas from the site of excision biopsy or in the contralateral breast (29).
The study has the following limitations: The current study included a small series of patients. Only 31.5% (36/114) of total patients who were diagnosed with ADH through a US-guided VABB underwent additional excision biopsy. The remaining 78 patients (68.5%) were followed up at a 6-month to 1-year interval using MMG or US without undergoing additional excision biopsy.
To date, several previous studies have described factors associated with a decreased rate of upgrading to malignancy in patients with ADH. However, there are no established criteria for identifying patients who can be safely followed up without additional excision (23, 27, 30).
In conclusion, our results indicate that additional excision biopsy is recommended to reduce the rate of upgrading to malignancy in patients who were diagnosed with ADH through a US-guided VABB.
Footnotes
↵* These Authors contributed equally to this work.
Authors’ Contributions
HLP, BY, and JES designed the study. HLP, JYK, JYS, ES, SN, and JHK collected the data. HLP, and SN performed the data analysis. HLP, and JES drafted the manuscript. JYK, ES, JYS, SK, and BY edited the article. All Authors approved the final content for journal submission and publication.
Conflicts of Interest
The Authors have nothing to declare in relation to the current work.
- Received January 26, 2022.
- Revision received February 26, 2022.
- Accepted February 28, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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