Management of Lobular Neoplasia Diagnosed by Core Biopsy

Lobular neoplasia (LN) involves proliferative changes within the breast lobules. LN is divided into lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia (ALH). LCIS can be further subdivided into three subtypes: classic LCIS, pleomorphic LCIS, and LCIS with necrosis (florid type). Because classic LCIS is now considered as a benign etiology, current guidelines recommend close follow-up with imaging versus surgical excision. The goal of our study was to determine if the diagnosis of classic LN on core needle biopsy (CNB) merits surgical excision. This is a retrospective, observational study conducted at Mount Auburn Hospital, Cambridge, MA, from May 17, 2017, through June 30, 2020. We reviewed the data of breast biopsies conducted at our hospital over this period and included patients who were diagnosed with classic LN (LCIS and/or ALH) and excluded patients having any other atypical lesions on CNB. All known cancer patients were excluded. Of the 2707 CNBs performed during the study period, we identified 68 women who were diagnosed with ALH or LCIS on CNB. CNB was performed for an abnormal mammogram in the majority of patients (60; 88%) while 7(10.3%) had an abnormal breast magnetic resonance imaging study (MRI), and 1 had an abnormal ultrasound (US). A total of 58 patients (85%) underwent excisional biopsy, of which 3 (5.2%) showed malignancy, including 2 cases of DCIS and 1 invasive carcinoma. In addition, there was 1 case (1.7%) with pleomorphic LCIS and 11 cases with ADH (15.5%). The management of LN found on core biopsy is evolving, with some advocating surgical excision and others recommending observation. Our data show a change in diagnosis with excisional biopsy in 13 (22.4%) of patients with 2 cases of DCIS, 1 invasive carcinoma, 1 pleomorphic LCIS, and 9 cases of ADH, diagnosed on excisional biopsy. While ALH and classic LCIS are considered benign, the choice of ongoing surveillance versus excisional biopsy should be made with shared decision making with the patient, with consideration of personal and family history, as well as patient preferences.


Introduction
Lobular neoplasia involves proliferative changes within the breast lobules. Tis fnding is classifed as ALH or LCIS based on lobular involvement (>50% of the lobular region involved in LCIS), degree of lobular distension (more than benign lobules), and extent of lobule involvement (more than 50% acini involved in LCIS), and often the acinar lumen is occluded in LCIS. LCIS is subdivided into three subtypes: classic LCIS, pleomorphic LCIS, and forid LCIS ( Figure 1). Pleomorphic LCIS and forid LCIS display solid proliferation of dyscohesive neoplastic cells within terminal duct lobular units (TDLUs) similar to classic LCIS but difer with regard to the degree of nuclear atypia and/or lobular acinar expansion [1]. Genomic profling of diferent types of LCIS showed that pleomorphic LCIS and forid LCIS contain genetic alterations characteristic of lobular neoplasia; however, these variants are distinguished from classic LCIS reported in the literature by their highly recurrent ERBB2 alterations [2].
LCIS was frst defned in 1941, and since then the status of LCIS has changed from a premalignant lesion to a risk marker, meaning that patients diagnosed with LCIS are at increased risk of developing invasive breast cancer [3,4]. Management guidelines for LN are evolving and vary across institutions. As per the 2017 American Joint Commission of Cancer staging manual, classic LCIS is now considered as a benign lesion. Current NCCN guidelines state that a core biopsy showing classic LCIS can be managed without surgical excision, but that excision should be considered on a case-by-case basis. When surgical excision is not performed, close follow-up with mammogram and breast MRI screening every 6 to 12 months is recommended [5,6]. Patients are also counseled regarding breast cancer risk reduction strategies such as chemoprevention [7].
Concerning features such as a high degree of atypia or necrosis seen on core needle biopsy (CNB) favor surgical biopsy for a full evaluation of the tissue [8]. In addition, the degree of concordance between the CNB and previous imaging studies can help guide further management; histopathological results that are inconsistent with the mammographic appearance of the lesion would favor surgical excision [8]. Pleomorphic LCIS or forid LCIS with marked nuclear pleomorphism is of greater concern due to the potential to progress to infltrating pleomorphic lobular carcinoma and, as such, is treated like ductal carcinoma in situ and warrants surgical excision with clean margins and postoperative radiation [7][8][9][10]. Multiple foci LCIS (LCIS involving 4 terminal ductal units on CNB) is also associated with an increased risk of malignancy and warrants excisional biopsy [8].
Te aim of this study was to examine the results of surgical excision after core biopsy showing the diagnosis of ALH or classic LN by breast core needle biopsy (CNB) to determine the frequency of change in diagnosis with resection of additional tissue.

Methods
Tis is a retrospective observational study that was conducted at Mount Auburn Hospital, Cambridge, MA, from May 17, 2017, until June 30, 2020. Institutional Review Board approval for chart review was obtained. We reviewed the data of 2707 breast CNBs conducted at our hospital and included all patients who were diagnosed with LN only on CNB (classic LCIS and/or ALH). Patients were excluded if the CNB showed invasive carcinoma, ductal carcinoma in situ (DCIS), pleomorphic or forid LCIS, a radial scar, ADH (atypical ductal hyperplasia), other atypia, or papillary lesions. Cases with radiologic-pathologic discordance were also excluded because these cases would routinely be excised. In addition, cases where the diagnosis of ALH or LCIS was made on breast reduction or patients having history of concurrent or previous breast carcinoma were excluded. Clinical information including the age, gender, race, and ethnicity was collected from our electronic medical records. Details of imaging were also collected. Results of the excisional biopsy were reviewed by the pathologist and recorded.

Results
We identifed 68 female patients who were diagnosed with lobular neoplasia on CNB (Table 1). Our population's mean age was 55 years old, and the majority of patients were 50 years or older (47; 69%). Te mean body mass index (BMI) was 25.7. Te majority (78%) of patients were Caucasian, 5.9% were Asian, 4.4% were African American, and 11.8% did not have documentation of race. Most of the patients were non-Hispanic (86.8%). Patients with a personal history of breast cancer were excluded from the study as per our Methods section. However, a substantial number of the patients did have a family history of breast cancer: 26% had a frst degree relative (mother or sister) with breast cancer and 60% had a second or third degree relative with breast cancer. Te majority of these patients, 42 (72%), had no history of prior biopsy, 11 had 1 prior biopsy (19%), 4 (7%) had 2 prior biopsies, only 1 (2%) had more than 2 prior biopsies. CNB was performed for an abnormal mammogram in the majority of patients (60; 88.2%), while 7 (10.3%) had an abnormal breast magnetic resonance imaging study (MRI) and 1 (1.5%) had an abnormal ultrasound. All patients had one site biopsied. Our radiologists' philosophy is to biopsy the most suspicious site and then plan for management of additional sites, if any, based on the results of the frst biopsy.
Out of the 3 patients found to have cancer on surgical excision, 2 of these had routine screening mammograms, while 1 was undergoing six-month follow-up evaluation. Of note, all 3 patients had a positive family history of breast cancer. All 3 patients were found to have calcifcations raising concerns for CNB. On CNB, 2 patients showed ALH, while another patient showed LCIS. On excisional biopsy, both the patients with ALH were found to have DCIS, while the patient with LCIS showed multifocal invasive carcinoma ( Table 2). Figure 2 demonstrates representative images of a patient with upstaging from LCIS to invasive carcinoma. Te imaging characteristics of all three upgraded patients were predominantly defned by calcifcations rather than a mass. Te calcifcations were defned as "coarse heterogenous" calcifcations, which are by defnition a Breast Imaging Reporting and Data System (BI-RADS) 4B lesion [11]. BI-RADS 4B lesions on mammography are lesions that have a 10-50% risk of malignancy. LN, in these situations, is concordant with coarse heterogeneous calcifcations. Tere is no one radiological fnding that can diferentiate LN from more invasive carcinomas or DCIS.

Discussion
Approximately 39 million mammograms are performed in the US yearly [12]. As the quality of mammographic screening has improved and additional screening such as ultrasound and MRIs are also increasing in use, it is inevitable that biopsy rates will also increase. It has previously been estimated that after routine screening, approximately 10% of patients will need a biopsy. Of those biopsied, 49.4% had second procedures, 20.1% followed with third procedures, and 10.0% had a fourth procedure [13].
With large numbers of benign biopsies being done and many of these showing risk markers such as ADH and LCIS, it is important to periodically reevaluate appropriate management of these lesions. As of 2017, as per the American Joint Commission on Cancer, classic LCIS on CNB is deemed a benign fnding, with no further recommendations for diagnostic or therapeutic intervention [14]. Tere is still variability in how this fnding is managed with some recommending surgical excision and others recommending radiological surveillance as the best practice for managing LCIS patients [9].
For patients with non-classic LCIS (pleomorphic and forid) on core biopsy, the rate of upgraded diagnosis to malignancy has been reported to be as high as 36% [15]. Patients with pleomorphic LCIS, in particular, are treated by some surgical oncologists with the same approach as for DCIS with complete excision, negative surgical margins, and postoperative radiation. Although this approach is not specifcally supported by NCCN guidelines, it is endorsed by the European Society of Medical Oncology (ESMO) guidelines [2,16,17]. However, as outcome data regarding treatment for pleomorphic and forid LCIS are lacking, a multidisciplinary case-based approach should be employed to agree on a treatment course for each patient [16].
A meta-analysis of 9 studies showed limited generalizability and signifcant uncertainty among LCIS management guidelines [10]. Diagnosis upstaging from LCIS to invasive breast cancer or to ductal carcinoma in situ ranges from 2% to 25% [10]. Metovic [20]. Tey demonstrated a 6.2% risk of conservative management failure. Tus, when conservative management is chosen, careful follow-up with imaging is needed. Although the percent of upstaging varies between reviews, there are themes regarding certain characteristics that are atypical for LCIS that, when found, warrant surgical excision as they are associated with an increased risk of upstaging [21]. A mass lesion, whether found radiographically or on physical exam, is generally inconsistent with LCIS and its presence makes further diagnostic workup more justifable [21]. Conversely, specifc factors such as a lesion size less than 1 cm in combination with the absence of residual calcifcations after biopsy were consistent with benign disease and the absence of upstaging [22]. In addition, certain patient characteristics that may predispose them to malignancy, such as family history, may be considered when deciding whether or not to pursue surgical intervention [23]. Recent guidelines from the American Society of Breast Surgeons recommend observation for LCIS and ALH diagnosed on CNB only if a specifc set of criteria is met: that there is concordance between the imaging and pathology results, the lesions are small volume without atypia or other high-risk features, and that serial follow-up and repeat imaging are performed [24]. Tere is increasing evidence that careful surveillance is a reasonable alternative to excisional biopsy in the majority of patients with LN on core biopsy [25]. However, in this retrospective study, we found that 5% of our cohort who met the abovementioned criteria of close follow-up had an upstage of their diagnosis. Te majority (91%) of these diagnoses were made on routine mammographic screening, which can impact the follow-up required thereafter [26]. An additional 17% of cases showed a change in diagnosis to pleomorphic LCIS or ADH, which can change the further management of these patients. We recommend that, in such cases, further risk factors should be considered, surgical excision should be ofered to these patients, and shared decision making with the patient should be an integral part of management. Family history enters into the decision-making process, and patients with a family history of breast cancer may be more anxious to proceed with biopsy as opposed to observation. As noted above, 26%    Te Breast Journal 7 of our patients had a frst degree relative (mother or sister) with breast cancer and 60% had a second or third degree relative with breast cancer. We acknowledge that our study has some limitations. We do not have additional information on the 2 patients who were lost to follow-up. Even though there was no evidence of missing the radiological targets, we cannot completely exclude the chances of a false negative, and thus close surveillance of these patients is warranted [27]. In addition, any patients with radiological-pathological discordance were excluded, as that would warrant further surgical workup. Due to the study's retrospective nature, we were also unable to review all of the histopathological slides of these patients. However, the reports were verifed before analyzing the results.

Conclusion
Our data show that 5% of patients, initially shown to have LN by CNB, and who then underwent excisional biopsy, were found to have malignant tumors. Careful radiologic and pathologic review of each case as well as consideration of family history and other risk factors is needed to evaluate whether to recommend excision or close surveillance. Decision to undergo surgical excision should be made through shared decision making with the patient, with the benefts of early detection weighed against the risks of undergoing an invasive procedure.

Data Availability
Deidentifed data can be requested from Dr. Pories at spories@mah.harvard.edu. Release of data would need to be approved by our IRB.

Disclosure
Chinmay Jani and Margaret Lotz are co-frst authors.

Conflicts of Interest
Te authors declare that they have no conficts of interest.

Authors' Contributions
Chinmay Jani and Margaret Lotz contributed equally to the paper.