Cases Of Lobular Carcinoma In Situ Research Articles

Abstract PO5-13-11: Quantitative Assessment of HER2 Expression in Intraductal Neoplasms of the Breast

Abstract HER2 (ERBB2) is an established prognostic and predictive marker for patients with invasive breast cancer and used in HER2-targeted therapy. The clinical and biological significance of expression of HER2 protein in patients with intraductal neoplasms of the breast is not well characterized. In this study, we used our HS-HER2 (High Sensitivity-HER2) which is a CAP/CLIA certified laboratory derived test (LDT) using quantitative immunofluorescence (QIF). We evaluated HER2 expression in DCIS (ductal carcinoma in situ), LCIS (lobular carcinoma in situ) and benign lesions to correlate with their clinicopathologic characteristics. Thirty- eight cases of DCIS, and fourteen cases of LCIS and thirty benign cases were selected from the Yale Pathology department archives and 252 ROIs (regions of interest) were annotated by a board-certified pathologist. DCIS is classified according to the three-tier nuclear grading system: low, intermediate, and high-nuclear grade. LCIS is classified as PLCIS (pleomorphic variant) and CLCIS (classic LCIS) according to the WHO classification of breast tumors. Serial sections of FFPE tumor specimens were used to accurately quantify the HER2 expression by the HS-HER2 assay and the acquisition by QuPath v.04 with Qymia extension. According to the LOD (limit of detection,3 amol/mm2), LOQ (limit of quantification, 9 amol/mm2) and LOL (limit of linearity, 23 amol/mm2) of the optimized HS-HER2 assay as performed in our CLIA lab shows a broad range of HER2 expression in both DCIS and LCIS lesions, ranging from 0.7 amol/mm2 to 111.4 amol/mm2 in DCIS and 3.6 amol/mm2 to 49.9 amol/mm2 in LCIS. High grade DCIS lesions express higher average HER2 levels (111.4 + 0.7 amol/mm2) than combined low and intermediate grade DCIS (77.9 +1.9 amol/mm2) with no significant difference between low/intermediate and high-grade DCIS. CLCIS lesions express higher average HER2 level (49.9 + 3.6 amol/mm2) than PLCIS (35.1 + 5.4amol/mm2) but again this is not statistically significant. HER protein expression is relatively low in benign lesions ranging from 0.8 to 8.4 amol/mm2. Using the HS-HER2 assay, our results show quantitative level HER2 levels in DCIS and LCIS breast lesions. These findings may be important as HER2 targeted therapies that work in gene-unamplified cancer (HER2 conjugated ADCs) gain broader usage in the clinic. Citation Format: Nay Nwe Nyein Chan, Haiying Zhan, Revekka Khaimova, Thazin Aung, Charles Robbins, Patricia Gaule, David Rimm. Quantitative Assessment of HER2 Expression in Intraductal Neoplasms of the Breast [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-13-11.

Immediate and delayed risk of breast cancer associated with classic lobular carcinoma in situ and its variants.

To determine the risk of breast cancer due to lobular carcinoma in situ (LCIS). This retrospective IRB-approved study identified cases of LCIS after percutaneous breast biopsy from 7/2005 to 7/2022. Excluded were cases with less than 2years of imaging surveillance or a concurrent ipsilateral breast cancer diagnosis within 6months of the LCIS diagnosis. Final outcomes of cancer versus no cancer were determined by pathology at surgical excision or the absence of cancer on imaging surveillance. A total of 116 LCIS lesions were identified. The primary imaging findings targeted for percutaneous biopsy included calcifications (50.0%, 58/116), MR enhancing lesions (25.0%, 29/116), noncalcified mammographic architectural distortions (10.3%, 12/116), or masses (14.7%, 17/116). Surgical excision was performed in 49.1% (57/116) and imaging surveillance was performed in 50.9% (59/116) of LCIS cases. There were 22 cancers of which 11 cancers were discovered at immediate excision [19.3% (11/57) immediate upgrade] and 11 cancers developed later while on imaging surveillance [18.6% (11/59) delayed risk for cancer]. Among all 22 cancers, 63.6% (14/22) occurred at the site of LCIS (11 at immediate excision and 3 at surveillance) and 36.4% (8/22) occurred at a location away from the site of LCIS (6 in a different quadrant and 2 in the contralateral breast). LCIS has both an immediate risk (19.3%) and a delayed risk (18.6%) for cancer with 90.9% occurring in the ipsilateral breast (63.6% at and 27.3% away from the site of LCIS) and 9.1% occurring in the contralateral breast.

DCIS and LCIS: Are the Risk Factors for Developing In Situ Breast Cancer Different?

Ductal carcinoma in situ (DCIS) is widely accepted as a precursor of invasive ductal carcinoma (IDC). Lobular carcinoma in situ (LCIS) is considered a risk factor for invasive lobular carcinoma (ILC), and it is unclear whether LCIS is also a precursor. Therefore, it would be expected that similar risk factors predispose to both DCIS and IDC, but not necessarily LCIS and ILC. This study examined associations with risk factors using data from 3075 DCIS cases, 338 LCIS cases, and 1584 controls aged 35-60, recruited from the UK-based GLACIER and ICICLE case-control studies between 2007 and 2012. Analysis showed that breastfeeding in parous women was protective against DCIS and LCIS, which is consistent with research on invasive breast cancer (IBC). Additionally, long-term use of HRT in post-menopausal women increased the risk of DCIS and LCIS, with a stronger association in LCIS, similar to the association with ILC. Contrary to findings with IBC, parity and the number of births were not protective against DCIS or LCIS, while oral contraceptives showed an unexpected protective effect. These findings suggest both similarities and differences in risk factors for DCIS and LCIS compared to IBC and that there may be justification for increased breast surveillance in post-menopausal women taking long-term HRT.

A Rare Case of Lobular Carcinoma in Situ Within a Fibroadenoma

Background: Fibroadenomas (FAs) are common benign breast tumors which account for 68% of all breast masses. They can be divided into simple and complex FAs. Though unusual, FAs can harbor invasive or in situ carcinomas, as well as high risk lesions such as lobular carcinoma in situ (LCIS) as we present in this case report.Case Presentation: In this case report, we are presenting a rare case of LCIS within a FA with a brief description of presentation, classification and radiological features.Conclusion: Carcinomas within FAs remain a diagnostic challenge. Despite being considered benign, FAs should still be closely monitored by ultrasound (US) as they can still harbor in situ or invasive carcinomas or high-risk lesions, including LCIS. Radiologists should always be aware and consider these as part of their differential diagnosis whenever benign looking masses have atypical features or presentation. The current management of LCIS detected within FA is still similar to LCIS found elsewhere in the breast.

Clinicopathological Features and Prognosis of Lobular Carcinoma <i>In Situ</i>

Purpose According to the American Joint Committee on Cancer’s 8th Edition Manual, lobular carcinoma in situ (LCIS) is no longer considered a malignant disease, although it may be a precursor to the development of breast cancer. The present study aimed to evaluate the clinicopathological features and prognosis of LCIS. Methods This study retrospectively analyzed clinicopathological features and prognosis data of LCIS among patients who underwent breast surgery at Severance Hospital, Seoul, South Korea from 1991 to 2016. Results Of the 47 patients, 49 cases of LCIS were confirmed by postoperative pathology. The mean patient age was 48.15±8.34 years. Most patients (81.6%) did not have palpable tumors at diagnosis, and 51.0% showed no microcalcification on mammography. Breast-conserving surgery was performed more frequently than total mastectomy (77.6% vs. 22.4%). The mean tumor size was 1.63±2.11 cm. There were only 3 cases of pleomorphic LCIS. Hormone receptor-positive tumors were noted in 47 cases, however, the hormone receptor status was unknown in the other 2 cases. There were no LCIS recurrences or deaths during the follow-up period (mean 56 months). Conclusion LCIS is often incidentally diagnosed without clinical symptoms, especially in women aged <50 years. The prognosis of LCIS is excellent in cases that are surgically treated. Keywords: Core needle biopsy; Lobular carcinoma in situ; Prognosis

Abstract PS16-03: Clonal relatedness of LCIS with synchronous and asynchronous invasive disease

Abstract Background: Lobular carcinoma in situ (LCIS) is typically clinically undetectable but is being increasingly diagnosed as a result of breast screening mammography and is often found associated with other breast pathologies such as invasive lobular breast cancer (ILC), invasive carcinoma of ductal /no special type (IDC) and ductal carcinoma in situ (DCIS). It is also considered a risk factor for the development of subsequent invasive breast disease. The aim of this study was to understand the genetic relationship between LCIS that presents with synchronous DCIS, IDC and/or ILC in order to ascertain whether the components have common precursors and also to understand the clonal relationship between LCIS and subsequent invasive disease. Methods: 25 cases of LCIS with synchronous ILC, 7 cases of LCIS with synchronous DCIS &amp; IDC, and 8 pure LCIS that developed a subsequent invasive recurrence were identified from the GLACIER study (MREC 06/Q1702/64). DNA was extracted from archival paraffin embedded tissue and underwent copy number analysis using either the Oncoscan™ Array (Affymetrix) or HumanCytoSNP FFPE-12 BeadChip (Illumina). Four of 7 cases of LCIS with synchronous DCIS &amp; IDC also underwent targeted sequencing using a custom 121 breast cancer-associated gene panel (SureSelectXT HS kit, Agilent Technologies). Clonal relatedness was assessed using a novel methodology based on the presence of shared copy number aberration breakpoints and mutations. Results: Of the 25 synchronous LCIS and ILC cases, 17 appeared related, 4 were ambiguous (sharing the typical lobular signature of 1q gain and 16q loss) and 4 demonstrated no evidence of relatedness. Of the 7 cases with synchronous LCIS, DCIS and IDC, all had copy number data available and 4 had mutation data available. In 3 cases the synchronous LCIS, DCIS and IDC were clonally related according to copy number and for two there was mutation data that supported this (one sharing PIK3CA and CDH1 mutations, the other a TP53 mutation). In two cases the LCIS was not related to the DCIS or IDC, but the DCIS and IDC were related to each other; while in one case LCIS was related to IDC but not to the DCIS by copy number but all components shared the same CHEK2 mutation. Finally in one case none of the three components were related to each other by copy number but the LCIS and IDC shared a PIK3CA mutation, albeit at much lower allele frequency in LCIS than in IDC. Of the 8 patients with pure LCIS, 4 developed an ipsilateral invasive recurrence of various combinations of morphologies: 1 ILC &amp; LCIS, 1 ILC &amp; DCIS, 1 IDC &amp; DCIS, 1 ILC &amp; IDC, and 4 a contralateral recurrence (1 tubular, 1 IDC, 2 ILC), with a median time to recurrence of 69 months (range 34-175). The primary LCIS was related to at least one component of the recurrent disease in all four ipsilateral cases; in two the primary LCIS and all components of the recurrent disease were related, and in the remainder we observed a variety of putative evolutionary patterns. Conclusions: The majority (68%) of cases of synchronous LCIS and ILC appeared to be clonally related by copy number. 50% of cases of co-existing LCIS and IDC appeared to have a common clonal origin by either copy number or targeted sequencing. As these are genomically stable tumours, copy number data may also be underestimating relatedness. In the four cases of pure primary LCIS that developed an ipsilateral recurrence, different subtypes of breast cancer were noted as the recurrence morphology, supporting the historical view that LCIS is a risk lesion rather than a true precursor. However, in all cases the preceding LCIS was found to be related to at least one component of the subsequent invasive tumour including DCIS and IDC. This data shows that clonal relatedness between LCIS and both synchronous and asynchronous invasive disease and DCIS is more complex than previously thought, with LCIS acting as a precursor lesion even in some cases of IDC. Citation Format: Elinor Sawyer, Mateja Sborchia, Anargyros Megalios, Vandna Shah, Salpie Nowinski, Cloe Vassart, Anita Grigoriadis, Alastair Thompson, Ian Tomlinson, Rebecca Roylance, Sarah Pinder. Clonal relatedness of LCIS with synchronous and asynchronous invasive disease [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-03.

Management of high-risk breast lesions diagnosed on core biopsies and experiences from prospective high-risk breast lesion conferences at an academic institution.

The management of high-risk breast lesions diagnosed on image-guided core biopsy remains controversial. We implemented a high-risk breast conference attended by breast pathologists, imagers, and surgeons to prospectively review all contemporary cases in order to provide a consensus recommendation to either surgically excise or follow on imaging at 6-month intervals for a minimum of 2years. Between May, 2015 and June, 2019, 127 high-risk lesions were discussed. Of these 127 cases, 116 had concordant radiology-pathology (rad-path) findings. The remaining 11 patients had discordant rad-path findings. Of the 116 concordant cases, 6 were excluded due to lack of the first imaging follow-up until analysis. Of the remaining 110 patients, 43 had atypical ductal hyperplasia (ADH), 12 had lobular carcinoma in situ (LCIS), 19 had atypical lobular hyperplasia (ALH), 33 had radial scar (RS), 2 had flat epithelial atypia (FEA), and 1 had mucocele-like lesion (ML). We recommended excision for ADH if there were > 2 ADH foci or < 90% of the associated calcifications were removed. For patients with LCIS or ALH, we recommended excision if the LCIS or ALH was associated with microcalcifications or the LCIS was extensive. We recommended excision of RS when < 1/2 of the lesion was biopsied. We recommended all patients with FEA and ML for 6-month follow-up. Following conference-derived consensus for excision, of the 27 ADH excised, 9 were upgraded to invasive carcinoma or ductal carcinoma in situ. Of the six LCIS cases recommended for excision, none were upgraded. Nine excised radial scars revealed no upgrades. Additionally, 3 patients with ADH, 2 with ALH, 1 with LCIS, and 2 with RS underwent voluntary excision, and none were upgraded. All other patients (13 with ADH, 5 LCIS, 17 ALH, 22 RS, 2 FEA and 1 ML) were followed with imaging, and none revealed evidence of disease progression during follow-up (187-1389days). All 11rad-path discordant cases were excised with 2 upgraded to carcinoma. The results of this prospective study indicate that high-risk breastlesions can be successfully triaged to surgery versus observation following establishment of predefined firm guidelines andperformance of rigorous rad-path correlation.

Occurrence of Occult Malignancies in Reduction Mammoplasties.

ObjectivesPatients undergoing reduction mammoplasty (RM) bear the risk of having occult breast cancer nests. The detection rate of malignant neoplasms in the resected specimens, varies greatly in the literature. The aim of our present study was to analyze risk factors and evaluate histopathological findings in our cohort of patients who underwent RM towards our center.Material and methodsIn this retrospective single center study we analyzed 559 female patients [median age 35.99 (±13.34)] who underwent RM between 2000 and 2010. The presence of carcinoma and ductal- (DCIS) or lobular carcinoma in situ (LCIS) were considered as pathological findings. Body mass index (BMI), age, surgical technique and mass of resected tissue were included into the analysis.ResultsThere were 6 cases of occult neoplasia (1.08 %) including 2 cases of breast cancer, one multicentric DCIS and 3 cases of LCIS (0.54 %) in 559 patients. Patients with breast cancer showed a significant increased median age: 49y median (IQR ± 18) vs. 35y (IQR ± 21) (p = 0.004) and a trend towards increased BMI: 25.88 median (IQR ± 7.3) vs. 24.50 (IQR ± 4.09) (p = 0.219), compared to patients without pathological results. One patient with occult carcinoma had a negative preoperative mammography, a patient with LCIS a negative preoperative breast ultrasound.ConclusionsIn our study the occurrence of occult neoplasia was associated with increased age and showed a trend towards increased BMI when compared to patients without pathological findings. The study demonstrates the necessity of thorough medical history, preoperative diagnostic screening and histopathological analysis of all resected specimens.

Treatment and survival outcomes of lobular carcinoma in situ of the breast: a SEER population based study.

Lobular carcinoma in situ (LCIS) represents 5.3% of in situ specimens, and is thought to carry a low risk for developing to the invasive lobular breast cancer (ILC). There is still no standard care approach for patients with LCIS. We aimed to define the impacts of surgical and radiation intervention on survival outcomes of LCIS. LCIS cases from 2004 to 2013 of the recent Surveillance, Epidemiology, and End Results (SEER) database were analyzed. Clinicopathologic features were analyzed in 16002 patients between 2004 and 2013. Treatment modalities included no surgery (NS), lumpectomy alone (LA), lumpectomy with radiation treatment (LRT), mastectomy alone (MA) and mastectomy with radiation treatment (MRT). The overall survival (OS) was calculated by the Kaplan-Meier method. Univariate and multivariate analyses were performed using the variables of treatment, race, hormone receptor status, grade and age. Among 16002 patients, median follow-up was 54 months. Patients treated with LA had superior OS for NS (P = 0.001), MA (P < 0.001) and MRT P = 0.018). LRT only had superior OS for MRT (P = 0.009). There was no statistically significance between LA and LRT (P = 0.317). Improved OS was also correlated with younger age (P < 0.001), progesterone receptor positive (P = 0.001). Black patients had the worst OS (P < 0.001). There was no obvious survival difference among grade groups (P = 0.536). The LCIS patients treated with LA or LRT had better survival comparing with other groups. Considering the medical expense and the risk of radiotherapy, LA may be the most appropriate therapy for patients with LCIS.

Prognostic Value of Coexisting Lobular Carcinoma In Situ With Invasive Lobular Carcinoma.

Recent studies show that lobular carcinoma in situ (LCIS) and invasive lobular carcinoma (ILC) share similar genetic molecular biology. There are increasing concerns regarding the biological significance of LCIS. The aim of this study is to investigate whether the presence of coexisting LCIS in ILC affects tumor biology and behavior and to correlate it with other clinicopathologic parameters. In this study, 254 cases of ILC were included. Clinicopathologic parameters and immunohistochemical stains for estrogen receptor (ER), progesterone receptor (PR), E-cadherin, human epidermal growth factor receptor (HER2), and MIB-1 of 254 ILC cases were retrieved. The patient with ILC and coexisting LCIS were compared with pure ILC cases with respect to different clinicopathologic parameters. Of the 254 cases, 107 cases were pure ILC and 147 cases were ILC with coexisting LCIS. Seventy-six (76/184, 41.32%) cases showed axillary lymph node metastases. Lymph node metastasis was absent in 108 cases, micrometastasis was present in 5 cases, and stage N1, N2, N3 in 51, 5, and 15 cases, respectively. Nodal involvement, locoregional and distant recurrence of ILC with LCIS were less frequent compared with ILC without LCIS with P-value of 0.034 and 0.007, respectively. The presence of coexisting LCIS in ILC predicted higher disease-free survival (DFS) compared with pure ILC (P=0.034, log-rank test). When divided into different strata, ER-positive ILC cases with associated LCIS cases showed better DFS than ER-positive pure ILC cases (P=0.021, log-rank test). Similarly, ILC cases with LCIS in patient less than 50 years showed better DFS than the patient less than 50 years with pure ILC (P=0.045, log-rank test). In conclusion, ILC coexisting with lobular carcinoma in situ (ILC+LCIS) is characterized by less nodal involvement, lower locoregional, and distant recurrence and better DFS than pure ILC. When divided into different strata, ER-positive and less than 50-year groups with ILC+LCIS show even significant better DFS than pure ILC. These findings suggest that there is biological significance of coexisting LCIS in ILC and that this may have more effect on tumor aggressiveness in certain strata of ILC.

Fibroadenoma with an unexpected lobular carcinoma in situ: A case report and review of the literature.

Fibroadenoma (FA) is the most common type of breast lesion in young female individuals. Although malignant transformation in FA is rare, there is evidence of an association with breast carcinoma, particularly in middle-aged females with associated risk factors, such as a strong family history and/or BRCA-1/2 mutations. The current study presents the case of a 44-year-old female exhibiting lobular carcinoma in situ (LCIS) arising within an FA. Over the previous 20 years, numerous lumps were detected in the patient's breasts, all of which were clinically diagnosed as FA and expectantly managed. One year prior to presentation, the patient's father was diagnosed with esophageal cancer, older sister with kidney cancer and the patient herself with a benign ovarian teratoma. The patient presented with one lump in each breast and monitoring was performed using ultrasonography (US). US detected an increase in the size of the two lumps and analysis of the images was used to propose a diagnosis of FA. Therefore, a lumpectomy was performed. Analysis of the frozen section indicated a diagnosis of FA in the right breast, however, a 5-mm LCIS was identified within the FA of the left breast. Subsequent to the identification of three additional lumps in the left breast, a left mastectomy was performed. During a five-year follow-up period, no local recurrence or contralateral breast carcinoma occurred. The present study showed that FAs containing foci of carcinoma in situ can be indistinguishable from benign lesions following imaging, therefore, despite the incidence of carcinoma within FA is estimated at 0.1-0.3%, it should be considered a long-term risk factor for invasive breast cancer. The present describes a case of LCIS arising within an FA and conducts a review of the relevant literature.

Underestimation of Atypical Lobular Hyperplasia and Lobular Carcinoma in Situ at Stereotaxic 11-Gauge Vacuum-Assisted Breast Biopsy

The aims of this study are to determine the frequency of diagnosis of atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS) at stereotaxic-guided 11-gauge vacuum-assisted breast biopsy (VABB) and to assess the rate of underestimation of these at subsequent surgical excision and follow-up. Moreover, we aimed to define clinical, radiological and histological features of nonpalpable lesions in core biopsies that predict the lesion upgrade. Retrospective review of 11-gauge VABB was performed to identify the underestimation rate of nonpalpable lesions diagnosed as ALH or LCIS at VABB. Thirteen cases of ALH and 36 cases of LCIS were sent to surgery, 29 cases of ALH and 14 cases of LCIS were sent to follow-up. The clinical, mammographic and histologic features were assessed. The correlation between mammographic BI-RADS score and histological B-classification for both ALH and LCIS lesions were performed by Pearson's test. Of 1,765 patients enrolled, lobular lesions (ALH and/or LCIS) occurred in 82 cases, and underestimation arose in 9 (10.9%). Two cases of underestimated ALH were upgraded to invasive lobular carcinoma and one to invasive ductal carcinoma. One case of underestimated LCIS was upgraded to ductal carcinoma in situ, two to invasive ductal carcinoma and three to invasive lobular carcinoma. The histology of the core and surgical specimens were compared. A significant difference was seen in the BI-RADS score (4–5 in 91% of underestimated lesions), and the size of the lesions (≥ 1.5 cm) for underestimated cases versus accurately diagnosed cases (p&lt;0.001). Further significant parameters predictive for malignancy were the incomplete lesion removal by VABB and the presence of associated different breast lesions in the specimen. In conclusion, as far as ALH is concerned, we propose surgery as first choice when at least one of the following condition is respected: positive history for breast carcinoma, lesion &gt;1.5cm, co-presence of high-risk lesions in the sample, signs of ductal involvement, high histological grading for atypia and follow-up in the other cases. Surgery is recommended in all cases of LCIS:

Long-Term Follow-up of Lobular Neoplasia (Atypical Lobular Hyperplasia/Lobular Carcinoma In Situ) Diagnosed on Core Needle Biopsy

Lobular neoplasia (LN) includes atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS). LN often is an incidental finding on breast core needle biopsy (CNBx) and management remains controversial. Our objective was to define the incidence of malignancy in women diagnosed with pure LN on CNBx, and identify a subset of patients that may be observed. Patients diagnosed with LN on CNB between January 1993 and December 2010 were identified. Patients with an associated high-risk lesion or ipsilateral malignancy at time of diagnosis were excluded. All cases were reviewed by dedicated breast pathologists and breast imagers for pathologic classification and radiologic concordance, respectively. The study cohort was comprised of 184 (1.3 %) cases of pure LN (147 ALH, 37 LCIS) from 180 patients. Pathologic-radiologic concordance was achieved in 171 (93 %) cases. Excision was performed in 101 (55 %) cases and 83 (45 %) were observed. Mean follow-up was 50.3 (range, 6-212) months. Of cases excised, 1 of 81 (1.2 %) ALH and 1 of 20 (5 %) LCIS cases were upstaged to ductal carcinoma in situ (DCIS) and invasive lobular carcinoma (ILC), respectively. Only 1 of 101 (1 %) concordant lesions was upstaged on excision. Of the cases observed, 4 of 65 (6.2 %) developed ipsilateral cancer during follow-up: 1 of 51 (2 %) case of ALH and 3 of 14 (21.4 %) cases with LCIS (2 ILC, 2 DCIS). During follow-up, 2.9 % (4/138) patients with excised or observed LN developed a contralateral cancer. These data support that not all patients with LN diagnosed on CNB require surgical excision. Patients with pure ALH, demonstrating radiologic-pathologic concordance, may be safely observed.

The Significance of Lobular Carcinoma In Situ and Atypical Lobular Hyperplasia of the Breast

The significance of lobular neoplasia (LN), lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia (ALH)) found at core needle biopsy (CNB) of the breast remains uncertain. There is a consistent risk of underestimating malignancy after the diagnosis of LN on CNB. The aim of this study was to determine if patients with a CNB result of LN need surgical excision. Patients were identified by searching the institutions pathology database for the terms "lobular carcinoma in situ" and "atypical lobular hyperplasia" over 20 years. Excluded from this study were those with core needle biopsy (CNB) results of ductal carcinoma in situ, atypical ductal hyperplasia, radial scar, or papilloma. Upgrade was defined as final surgical pathology of invasive carcinoma and/or ductal carcinoma in situ that was directly correlated to the site of the initial biopsy containing LN. LN was found at CNB in 285 patients, and 71 % (n = 201) had subsequent surgical excisions. All patients with pleomorphic LCIS (pLCIS) underwent surgical excision. Following patients with pLCIS, patients with the diagnosis of LCIS were most likely to undergo surgical excision (80 %). Final pathology of the surgically excised specimens confirmed LN in 72 % (n = 144). Also, 13 % (n = 26) of the operated patients were upgraded to malignancy, including 8 % of ALH and 19 % of LCIS cases. This is the largest series of surgical excisional pathology following LN on CNB ever reported. The likelihood of finding malignancy at surgical excision after CNB showing LN was 13 %. Patients with the diagnosis of LN on CNB should be considered for surgical excision.

Management of Patients Diagnosed With Lobular Carcinoma in Situ at Needle Core Biopsy at a Community-Based Outpatient Facility

The objective of our study was to show the importance of surgical excision after the diagnosis of lobular carcinoma in situ (LCIS) based on needle core biopsy. Retrospective evaluation of all cases of LCIS diagnosed at needle core biopsy from 2000 to 2011 was performed; 60 patients with 64 diagnoses of LCIS comprise the cohort. Data recorded included patient demographics, patient presentation, breast density, personal and family histories of breast cancer, lesion characteristics, biopsy method, and correlation of core results with surgical pathology or follow-up imaging. The pathology facility was recorded for all biopsies because the specimens from open surgical biopsy were frequently reviewed by a different laboratory. A total of 60 patients with 64 diagnoses of LCIS comprised the study cohort. The patients ranged in age from 36 to 93 years (average, 55 years). The lesions consisted of 39 calcifications, two masses with calcium, 10 masses, two asymmetries, two architectural distortions, two architectural distortions with calcifications, and seven MRI enhancements. Mammography detected lesions in 84% of the cases (n = 54) and 16% (n = 10) were not visualized. Sonography detected lesions in 30% of the cases (n = 19) and 70% (n = 45) were sonographically occult. Needle core biopsy was performed in all cases: 49 stereotactic biopsies (77%), 12 ultrasound-guided biopsies, and three MRI-guided biopsies. All but one case proceeded to surgery. Open surgical biopsy revealed 21 cancers (33%); of the remaining cases, 53% of the cases (n = 33) were atypical or high risk and 14% (n = 9) were benign. The diagnosis of LCIS at needle core biopsy, in this small study, revealed that 84% of lesions either were malignant or were atypical or high risk at surgery, of which 33% were found to be carcinoma. Our findings suggest that LCIS should be excised when noted at core biopsy.

Is There a Low-Grade Precursor Pathway in Breast Cancer?

Newly proposed models of breast tumorigenesis suggest that low- and high-grade lesions have distinct tumor progression pathways. Our objective was to examine the relationship between histologic grade and molecular subtype in women with lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS) who developed subsequent ipsilateral invasive breast cancers. Patients who underwent surveillance for classical LCIS (1994-2007) and those followed after lumpectomy±radiation for DCIS (1991-2004) who developed subsequent ipsilateral invasive cancers and had available tissue blocks were included. ER/PR/HER2 surrogates were used for molecular subtype. Material was available for 27 patients with classical LCIS who developed ipsilateral invasive cancer (12 invasive ductal cancer [IDC], 14 invasive lobular, 1 mixed), and 26 patients with DCIS (12 low-grade [LG], 14 high-grade [HG]) who developed ipsilateral IDC. No difference in age at diagnosis or median time to invasive cancer existed between groups with LCIS and DCIS. When stratified by grade, 0 of 12 LG-DCIS developed LG-IDC (3 grade II; 9 grade III), and only 1 of 12 LCIS patients who developed IDC had LG-IDC. Thirteen (93%) patients with HG-DCIS developed HG-IDC. In contrast, molecular subtype was maintained in 23 of 27 (85%) cases of LCIS and in 18 of 26 (69%) cases of DCIS. These data do not support a low-grade precursor pathway characterized by LCIS and LG-DCIS. ER/PR and HER2 status have a high rate of concordance between in situ and subsequent invasive lesions. Additional studies of metachronous in situ and invasive lesions are needed to better understand pathways of breast tumorigenesis.

The Florid Subtype of Lobular Carcinoma In Situ: Marker or Precursor for Invasive Lobular Carcinoma?

Lobular carcinoma in situ (LCIS) is considered a risk factor-not a precursor-for both invasive lobular and ductal carcinoma. Florid LCIS (F-LCIS) is an architectural subtype of LCIS that does not express E-cadherin, yet has the histologic and often radiographic appearance of solid-type ductal carcinoma in situ (DCIS). Since DCIS is considered a precursor to invasive ductal carcinoma, should F-LCIS be considered a precursor to invasive lobular carcinoma (ILC)? Review of an institutional database identified cases of LCIS and solid-type DCIS diagnosed by excisional biopsy, segmentectomy, or mastectomy between 1991 and 2000 to determine the prevalence of associated invasive breast cancer. Archival specimens were evaluated for florid and nonflorid LCIS, nuclear grade of LCIS, and the presence and subtype of invasive breast cancer. Solid-type DCIS that lacked E-cadherin expression was classified as F-LCIS. Of 210 consecutive specimens of LCIS examined, 171 had nonflorid LCIS (81%) and 39 had F-LCIS (19%). Nonflorid LCIS had a diffuse pattern, whereas F-LCIS appeared as discrete foci adjacent to ILC. An invasive component was identified with 87% of F-LCIS lesions versus 73% of nonflorid LCIS lesions (P = 0.064); this component was lobular in 100% of F-LCIS lesions versus 82% of nonflorid LCIS lesions, a significant difference (P = 0.0044) that persisted when the analysis was adjusted for nuclear grade (P = 0.0082). Its close spatial relationship to an invasive component and increased association with ILC suggest that F-LCIS may be a precursor for ILC.

Abstract P3-09-02: MicroRNA Expression Analysis in Lobular Neoplasia

Abstract Background: Lobular carcinoma in situ (LCIS) is a diffuse bilateral disease and is considered a marker for increase risk for development of invasive breast cancer but there is no direct measure of risk. MicroRNAs (miRNAs), are regulators of gene expression which have shown utility as markers of diagnosis and prognosis in cancer. We studied miRNA patterns in lobular neoplasia (LN) to characterize the miRNA profile of LN and to determine if specific expression patterns of miRNA correlated with risk for progression of LCIS Material and Methods: Formalin fixed parrafin embedded (FFPE) tumor blocks from Montefiore Hospital Bronx NY were microdissected under a light microscope prior to RNA extraction and quantification on a bioanalyzer. For profiling of miRNAs we tested our Illumina™ beadarray miRNA DASL assay with RNA extracted from 1 case of LCIS, 1 case of LCIS synchronous with invasive lobular cancer (ILC), 1 case of ILC alone and normal breast tissues as controls. We identified 41 miRNAs differentially expressed between normal and LN. We selected 8 miRNAs with the most characteristic differential expression between benign breast and LN and validated their expression in 45 FFPE breast specimens using the Taqman miRNA quantitative RT-PCR assays. The 45 cases included 9 normal breast, 10 LCIS alone, 8 LCIS from pts with synchronous ILC and the synchronous ILC and 10 ILC alone. We correlated results of miRNA profiles with type of LCIS (classic vs pleiomorphic vs LCIS with necrosis) and with development of another more significant breast cancer in pts with LCIS. Results: The 8 miRNAs which appeared the most deregulated in LN were miR-329, miR-486, miR-375, Mir -182/183/96 cluster, miR-187 and miR-10a. The following significant correlations were observed: 1) Of 18 LCIS samples there were 3 cases of pleiomorphic LCIS (PLCIS). The highest levels of mir-375 were observed in the 3 cases of PLCIS — The average fold increase of miR-375 was 70 fold in PLCIS and the average fold increase in classic LCIS was 7.0 fold when compared to normal breast.2) Mir-182/183/96 cluster — There were 3 pts with an initial diagnosis of LCIS alone who turned out to have a more clinically significant cancer (1 with contralateral DCIS, 1 with contralateral invasive ductal cancer and ipsilateral DCIS and 1 with ipsitlateral ILC). The highest elevations of these 3 miRNAs occurred in these 3 LCIS alone pts — The average fold increase in these 3 pts for each of the three miRNAs was 55,29 and 62 respectively and the average fold increase in the other LCIS alone pts was 6,7, and 7 respectively when compared to normal breast. 3) Mir-486- This miRNA was found to be down-regulated in synchronous ILC when compare to matched LCIS (p-value 0.035). Discussion: We provide a description of specific miRNA abnormailities observed in LN. Our results suggest that up-regulation of specific miRNAs (mir-375) may correlate with LCIS grade as well as risk for development of a more clinically significant cancer (mir-182,183 and 96). Down regulation of miRNAs (mir-486) suggest that molecular changes may be associated with cellular transitions and with progression to ILC. These preliminary results, which suggest that miRNA profiling of LCIS may help identify risk of breast cancer development, will be further investigated with a larger study Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-09-02.

Amplification of the prolactin receptor gene in mammary lobular neoplasia

The identification of lobular carcinoma in situ (LCIS) in a patient's specimen confers an appreciable increased risk of development of future invasive mammary carcinoma. However, the study of LCIS presents a challenge as it is usually only recognized in fixed specimens. Recent advances in high throughput genomics have made possible comprehensive copy number analysis of lesions such as this. Using array comparative genomic hybridization (aCGH), we characterized eight cases of lobular carcinoma (four invasive and four non-invasive) from microdissected samples of archival specimens and validated our results by quantitative real-time PCR (qRT-PCR). Immunohistochemistry (IHC) was performed on an independent set of 80 in situ ductal (DCIS) and lobular breast lesions to confirm our results. Amplification of the prolactin receptor gene (PRLr) was identified in 4/4 cases of LCIS by aCGH. We confirmed this amplification by qRT-PCR and demonstrated PRLr expression in 29/40 (73%) cases of lobular neoplasia by IHC. Amplification of PRLr was neither detected in 10 cases of DCIS nor in 5 areas of normal breast tissue by qRT-PCR and only 14/40 (35%) cases of DCIS showed PRLr expression by IHC (P = 0.0008). Our study suggests the prolactin receptor gene is a molecular target that may be important in the pathogenesis and progression of lobular neoplasia. Investigation of the status of this gene in cases of DCIS has indicated that it may not be as important in the progression of this type of breast cancer, supporting the view that lobular and ductal carcinomas may evolve along separate pathways.

Lobular Carcinoma In Situ Variants in Breast Cores: Potential for Misdiagnosis, Upgrade Rates at Surgical Excision, and Practical Implications

Differentiating ductal carcinoma in situ (DCIS) from lobular carcinoma in situ (LCIS) on core biopsy has important clinical implications. Lobular carcinoma in situ variants, including LCIS with necrosis and pleomorphic LCIS, share morphologic features with solid DCIS that may lead to misclassification. (1) To review all LCIS variants diagnosed in core biopsies at Northwestern University, Feinberg School of Medicine, and determine the frequency of misinterpretation of variant LCIS as solid DCIS in archival core biopsies, and (2) to determine the frequency of upgrade to invasive carcinoma or DCIS in the surgical excision. Consecutive core biopsies with original diagnoses of predominantly solid DCIS without invasion that were performed between January 2001 and December 2005 at Northwestern University, Feinberg School of Medicine, were selected for E-cadherin staining. The revised diagnosis of LCIS was based on E-cadherin negativity and morphology. The frequency of LCIS variants upgraded was then estimated from all core biopsies with original or revised diagnoses of pleomorphic LCIS or LCIS with necrosis. Among 75 cases of solid DCIS, 10 (13.3%) were reclassified as LCIS, including 9 variants (5 pleomorphic LCIS, 4 LCIS with necrosis) and 1 classic LCIS. Twenty-eight patients comprised the entire group of LCIS variant cases (both reclassified and originally diagnosed cases). Seven patients with LCIS variants (25%) were upgraded to invasive lobular carcinoma in surgical excision (4 of 11 cases of LCIS with necrosis [36%] versus 3 of 17 cases of pleomorphic LCIS [18%]). About one-tenth of solid DCIS diagnosed in core biopsies in the past may represent LCIS variants. These show a 25% upgrade to invasive lobular carcinoma in surgical excision. The distinction of an LCIS variant from DCIS is important because of its implications for radiation therapy, although it may not affect surgical management.