Reduction Mammoplasty Specimens Research Articles

Benign reduction mammoplasty specimens for histopathology: A waste of money and resources?

Introduction: Contralateral symmetrising reduction mammoplasty can be performed at index breast cancer surgery, or as a delayed procedure. Patients have recent diagnostic imaging or ongoing imaging surveillance. Many are also on systemic treatment. At present these mammoplasty specimens are sent for histopathology. Current literature states the incidence of cancer in cosmetic reduction mammoplasty is 0.23% (0-2.8%), presence of atypical lesions is 0.8% (0.3-5%). This study reports on outcomes and cost implications of histopathological analysis for symmetrising reduction mammoplasty.

Abstract P3-13-03: Heterozygous BRCA1 mutation influences alternative splicing in human benign mammary organoids

Abstract Background: Women carrying a germline BRCA1 mutation, have 60% risk of developing breast cancer during their lifetime and frequently develop triple-negative, basal-like, aggressive breast tumors. Humans produce around 150,000 different proteins from their 25,000-30,000 genes. This is accomplished by alternative splicing (AS). We hypothesized that AS in BRCA1 mutation carriers is different from those women with wild type BRCA1, therefore, we examined AS, expression of genes encoding splicing factors, and enrichment of binding motifs for RNA-binding proteins in BRCA1 carriers (BRCA1mut/+) and controls (BRCA1 normal). Methods: Prophylactic mastectomy (BRCA1mut/+) and reduction mammoplasty (BRCA1 normal) specimens were collected at Prentice Women’s Hospital of Northwestern Medicine under approval by Northwestern’s Institutional Review Board (NU15B07). We isolated organoids from these tissues, and cryopreserved them for future use. We selected organoids of premenopausal women, age-matched (28-46) without oral contraceptive usage within 3 years: BRCA1mut/+ (n=12) and BRCA1 normal (n=4). Organoids were maintained in complete MammoCult medium in ultra-low attachment plates at 37 °C, 5% CO2 for 72 hrs, and harvested for RNA extraction (NucleoSpin RNA Plus, TaKaRa). 100 ng of total RNA (RIN 7+) were used for RNA sequencing assay with the KAPA mRNA Hyper Prep Kit (Roche Corporate) and NovaSeq 6000 for 100b paired-end sequencing (Illumina, Inc). The preprocessed reads were aligned to the human genome (hg38) using STAR. Differential expression analysis (DESeq2, nominal p-value < 0.05) and pathway analysis (GSEA, size ≥30, NES >2, FDR q-value <0.05, and enriched genes ≥ 5) were performed to compare BRCA1mut/+ with BRCA1 normal. We used rMATS- turbo v4.1.0 to perform multivariate analysis of transcript splicing and chose an FDR < 0. 05, to identify significant differential alternative splicing events. To determine which RNA binding proteins and splicing factors were employed in BRCA1mut/+ tissue, we examined the cis-regulatory motifs adjacent to splice sites using rMAPs. Results: BRCA1mut/+ organoids displayed 155 upregulated genes compared to BRCA1 normal organoids (P <0.05). Among top 20 enriched pathways, we identified that expression of mRNA spliceosome (POLR2L, U2AF2, NUP188, SNRPF, CSTF3, HNRNPM, SRSF2), and, in addition, cell cycle, oxidative phosphorylation, HIV infection, and protein metabolism genes were significantly upregulated in BRCA1mut/+ organoids. We identified significant differential AS events (FDR <0.05) between BRCA1mut/+ and BRCA1 normal organoids: 2159 genes (skipped exon), 433 genes (mutually exclusive exon), 325 genes (retained intron), 304 genes (alternative 3’ splice sites), 168 genes (alternative 5’ splice sites). RNA splicing analysis indicated that highly expressed genes (SRSF2, ALG3, AP1B1 and PMF1) in BRCA1mut/+ organoids were also alternatively spliced. In addition, many other serine/arginine-rich splicing factors (SRSF) themselves (SRSF1, 2, 3, 5, 6, 7) were alternatively spliced (skipped exon events). An examination of binding motifs of RNA-binding proteins with significantly increased expression in BRCA1 carriers revealed multiple significantly enhanced and silenced regions flanking exons involved in AS. Conclusions: Our data suggest that AS of BRCA1mut/+ mammary tissue significantly differ from BRCA1 normal tissue, and may alter RNA spliceosome activity, and consequently play a role in malignant transformation and warrant further study. Citation Format: Oukseub Lee, Mi-Ran Choi, Gannon Cottone, Priyam Patel, Susan E Clare, Seema A. Khan. Heterozygous BRCA1 mutation influences alternative splicing in human benign mammary organoids [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-13-03.

The importance of preoperative imaging methods in reduction mammoplasty

Breast reduction surgery is a common procedure in plastic surgery clinics, and there are varying practices regarding preoperative mammography and breast ultrasound in patients who have no history of cancer and no symptoms other than those caused by macromastia.In this study, we retrospectively analyzed the imaging findings of patients who presented to the plastic surgery outpatient clinic due to macromastia between January 1, 2006 and June 1, 2020 and underwent mammography and/or breast ultrasound for preoperative screening and breast magnetic resonance imaging for further examination. Patients with a history of breast cancer diagnosed prior to preoperative screening or any other breast disease were excluded. Radiologically suspicious findings were significantly more common in patients over 40 years of age and significantly less frequent in the group under 50 years of age. When the patients were grouped by the decade of life, the frequency of radiologically suspicious findings was significantly lower in the 20–29 group and significantly higher in the 40–49 and 50–59 groups. Malignancy was not detected by histopathological examination in any patient. Proliferative lesions were detected in 10 reduction mammoplasty specimens (2.4%) of 7 patients (3.1%).The correlation between radiological and histopathological findings may be weak in macromastia patients. Most suspicious radiological findings appear to be the population between 40 and 59 years of age .

Rate of Incidental Pathological Lesions ın Reduction Mammoplasty Specimens and Incidence of Invasive Breast Carcinoma Following Breast Reduction Operation.

Reduction mammoplasty (RM) is one of the most frequently performed surgical procedures. The incidental determination of significant pathologic lesions (SPL), that is precursor and malignant lesions, in RM specimens is rare. The aim of this study was to determine the frequency of SPL in RM specimens, to evaluate the relationship between SPL and clinicopathological factors, and to examine the incidence of invasive breast carcinoma forming in the remaining breast tissue during the postoperative follow-up period developing in patients after RM operation. This retrospective study included 874 females who underwent RM operation between January 2012 and January 2021. Demographic, clinicopathological findings, and preoperative radiological findings were recorded. The patients were followed up after the RM operation in respect of the first occurrence of breast cancer. Invasive carcinoma was determined in 0.2% and SPL in 3.5% in RM. The probability of SPL determination was greater in patients aged ≥ 40 years and with ≥ 4 paraffin blocks (p=0.038, p=0.01, respectively). No statistically significant difference was found between patients with and without SPL in respect of radiological findings (p=0.35). The mean postoperative follow-up period was 53.6 months, and invasive carcinoma was diagnosed during follow-up in 0.2% of all patients (6.9% of the patients with SPL). Age over 40 years and an increased number of sampled blocks were found to be factors increasing the possibility of the determination of precursor and malignant lesions in RM specimens. RM could decrease the risk of the development of breast cancer. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Prevalence of breast cancer in reduction mammoplasty specimens, in women of African origin: preliminary histology results at Mankweng and Polokwane hospitals

Abstract
 Introduction. We report the first study on the prevalence of breast cancer in reduction mammoplasty specimens conducted in Limpopo province, South Africa. The prevalence of breast cancer is relatively low among pre-menopausal African women. Worldwide prevalence has been reported to range between 0.1% and 4.5%. Patients requesting reduction mammoplasty fear that their breast enlargement may be caused by the disease. Reduction mammoplasty is a common operation performed by plastic and reconstructive surgeons globally, but is an uncommon operation in Limpopo.
 Aims and objectives. To determine the prevalence of breast cancer in reduction mammoplasty specimens and to record the pertinent characteristics.
 Method. A prospective study of 104 female patients requesting reduction mammoplasty from 2007–2014 at Polokwane and Mankweng hospitals. The outcome measures were weight of specimens and histological investigation for breast carcinoma, body mass index and jugular–nipple distances.
 Results. All patients were of African origin whose median age was 32.4 (16–53) years, and median weight of excised tissue was 3.4 (1.45–6.2) kg. The median weight of patients was 77 (63–92) kg. The median BMI was 34.5 (29.1–39.9) kg/m2. The median jugular–nipple distance was 39 (25–51) cm on the right and 41 (29–53) cm on the left breast. Histological investigation revealed normal breast tissue in 57 cases, fibroadenosis in 25 cases, and duct hyperplasia in 22 cases.
 Conclusion.
 Breast cancer was not detected.
 The study population was relatively young at a mean age of 32.4 (16–53) years, without personal nor family history of breast cancer.

The rate of incidental atypical and malignant breast lesions in reduction mammoplasty specimens.

Reduction mammoplasty (RM) is one of the most common plastic surgeries in the United States. We aimed to demonstrate the rate of incidental atypical and malignant breast lesions (AMBL) found in RM specimens and the impact of the number of submitted tissue sections on the rate of AMBL. We analysed our database for patients who had undergone reduction mammoplasty between 2000 and 2018. Patients with a history of breast cancer were excluded from the study. All pathology reports were analysed for AMBL (ALH, LCIS, FEA, ADH, DCIS, invasive carcinoma). The grossing protocol was to submit 10sections from each breast between 2000 and 2013 and six sections between 2014 and 2018. One hundred and sixty-nine of 5208 patients (3.3%) and 216 of 10340 RM specimens (2.1%) showed at least one AMBL. Nineteen (0.36%) patients had incidental cancer. The median age of patients with AMBL was significantly higher than patients without ABL (aged 59years versus 45years). There was no cancer in patients aged <30years. The age-controlled rate of overall AMBL as well as atypia and cancer only did not decrease by submitting fewer sections during the 2014-18 period compared to the 2010-13 period. Decreasing the number of tissue sections from 10 to six did not lead to a significant decrease in the rate of overall AMBL or cancer. Our data suggest that submitting six tissue sections from each breast for patients aged >30years and two sections from each breast for patients aged <30years would be sufficient.

Pathologic Evaluation of Breast Tissue From Transmasculine Individuals Undergoing Gender-Affirming Chest Masculinization.

Bilateral mastectomy for chest masculinization is one of the gender-affirming procedures for transmasculine individuals. To optimize gross handling protocols and assess histopathologic findings in transmasculine breast tissue specimens. We identified all gender-affirming mastectomies from 2015 to 2018. We sequentially identified reduction mammoplasty (RM) cases for macromastia from the same period as control. Significant findings were defined as atypical ductal or lobular hyperplasia (ADH, ALH), ductal or lobular carcinoma in situ (DCIS, LCIS), or invasive carcinoma. Significant findings were present in 6 of 211 gender-affirming mastectomies (2.8%) as follows: ADH (n = 5) and LCIS together with ALH (n = 1). By comparison, 19 of 273 RM specimens (7%) yielded significant findings as follows: ALH (n = 11), ADH (n = 4), LCIS (n = 2), DCIS (n = 1), and invasive lobular carcinoma (n = 1). In the gender-affirming group, 142 transmen underwent androgen therapy before surgery, of whom 2 had significant pathologic findings. Thirty and 41 individuals had a family history of breast cancer in the gender-affirming and RM group, of whom 1 and 3 individuals had significant pathologic findings, respectively. Our study demonstrates that we handle transmasculine mastectomy specimens by examining 2.8 times more slides on average than for RMs, with a 2.5 times lower rate of significant pathologic findings. Prior family history of breast cancer or the use of androgen therapy before surgery in gender-affirming individuals did not increase the risk of identifying significant breast lesions. We recommend submitting 4 tissue blocks per mastectomy for individuals undergoing gender-affirming breast surgery.

Qualitative and quantitative differences in estrogen biotransformation in human breast glandular and adipose tissues: implications for studies using mammary biospecimens

Because of its assumed role in breast cancer etiology, estrogen biotransformation (and interaction of compounds therewith) has been investigated in human biospecimens for decades. However, little attention has been paid to the well-known fact that large inter-individual variations exist in the proportion of breast glandular (GLT) and adipose (ADT) tissues and less to adequate tissue characterization. To assess the relevance of this, the present study compares estrogen biotransformation in GLT and ADT. GLT and ADT were isolated from 47 reduction mammoplasty specimens derived from women without breast cancer and were characterized histologically and by their percentages of oil. Levels of 12 unconjugated and five conjugated estrogens were analyzed by GC- and UHPLC-MS/MS, respectively, and levels of 27 transcripts encoding proteins involved in estrogen biotransformation by Taqman® probe-based PCR. Unexpectedly, one-third of specimens provided neat GLT only after cryosection. Whereas 17β-estradiol, estrone, and estrone-3-sulfate were detected in both tissues, estrone-3-glucuronide and 2-methoxy-estrone were detected predominately in GLT and ADT, respectively. Estrogen levels as well as ratios 17β-estradiol/estrone and estrone-3-sulfate/estrone differed significantly between GLT and ADT, yet less than between individuals. Furthermore, estrogen levels in GLT and ADT correlated significantly with each other. In contrast, levels of most transcripts encoding enzymes involved in biotransformation differed more than between individuals and did not correlate between ADT and GLT. Thus, mixed breast tissues (and plasma) will not provide meaningful information on local estrogen biotransformation (and interaction of compounds therewith) whereas relative changes in 17β-estradiol levels may be investigated in the more abundant ADT.

Incidental breast carcinoma: incidence, management, and outcomes in 4804 bilateral reduction mammoplasties.

Bilateral reduction mammoplasty is one of the most common plastic surgery procedures performed in the U.S. This study examines the incidence, management, and prognosis of incidental breast cancer identified in reduction specimens from a large cohort of reduction mammoplasty patients. Breast pathology reports were retrospectively reviewed for evidence of incidental cancers in bilateral reduction mammoplasty specimens from five institutions between 1990 and 2017. A total of 4804 women met the inclusion criteria of this study; incidental cancer was identified in 45 breasts of 39 (0.8%) patients. Six patients (15%) had bilateral cancer. Overall, the maximum diagnosis by breast was 16 invasive cancers and 29 ductal carcinomas in situs. Thirty-three patients had unilateral cancer, 15 (45.5%)of whichhad high-risk lesions in the contralateral breast. Twenty-one patients underwent mastectomy (12 bilateral and nine unilateral), residual cancer was found in 10 in 25 (40%) therapeutic mastectomies. Seven patients did not undergo mastectomyreceived breast radiation. The median follow-up was 92months. No local recurrences were observed in the patients undergoing mastectomy or radiation. Three of 11 (27%) patients who did not undergo mastectomy or radiation developed a local recurrence. The overall survival rate was 87.2% and disease-free survival was 82.1%. Patients undergoing reduction mammoplasty for macromastia have a small but definite risk of incidental breast cancer. The high rate of bilateral cancer, contralateral high-risk lesions, and residual disease at mastectomy mandates thorough pathologic evaluation and careful follow-up of these patients. Mastectomy or breast radiation is recommended for local control given the high likelihood of local recurrence without either.

Incidental atypical hyperplasia/LCIS in mammoplasty specimens and subsequent risk of breast cancer.

1561 Background: Proliferative breast lesions with atypia (atypical hyperplasia and lobular carcinoma in-situ (LCIS)) increase the risk of breast cancer (BC). Most cases are diagnosed in the context of an abnormal mammogram. Little is known about BC risk for patients with these lesions who are asymptomatic. Mammoplasty specimens allow us to study breast tissue in asymptomatic healthy women. We previously published the rate of atypia in the largest reported mammoplasty cohort. The aim of this study is to examine the risk of BC in the atypia cohort. Methods: Breast pathology reports were retrospectively reviewed for evidence of atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH) or LCIS in bilateral reduction mammoplasty specimens from five institutions within a single healthcare system between 1990 to 2017. Patients with prior or concurrent BC or prior atypia were excluded. Data was extracted from electronic medical records using natural language processing and manual review to assess subsequent risk of BC. Results: From our mammoplasty cohort of 4771 patients, 295 patients were found to have atypia (6.2%) at baseline. 40 of these patients were lost to follow-up and excluded from the study. For the remaining 255 patients, 13 had severe ADH bordering on ductal carcinoma in situ, 52 had LCIS, 119 had ALH, and 71 had ADH at baseline. The median age at baseline was 52.1 (range 17.9 – 74.3). With a median follow-up of 7.7 years, of the 255 patients 9 patients developed BC (8 invasive carcinomas, 1 ductal carcinoma in situ). 81.3% of the cohort did not receive chemoprevention. Only one patient out of the nine who developed BC received chemoprevention. The risk of developing BC among women with atypia at baseline was 0.5%, 2.9% and 4.1%, at 3, 5 and 10 years respectively. Conclusions: Patients with asymptomatic atypias found in reduction mammoplasty specimens appear to be at lower risk of developing BC than those diagnosed with atypia in the context of an abnormal mammogram. These results may provide guidance on how to manage this group of patients related to future screening and/or chemoprevention.

Incidental Lesions Detected in Reduction Mammoplasty Specimens

The incidence of breast lesions detected in reduction mammoplasty specimens varies with patients’ previous history of breast cancer, patients’ age, and the number of submitted pathological sections. The incidence of proliferative lesions with atypia including invasive carcinoma varies in different studies between 0.2% and 1.1%. In a retrospective review, 392 patients who underwent reduction mammoplasty mainly for symptomatic macromastia or breast symmetry were included in this study. All specimens of reduction mammoplasty were submitted for pathological examination and at least four tissue sections were taken for each breast. Among 392 patients, pathological examinations revealed proliferative lesions with atypia in 7 patients (1.7%) and invasive carcinoma in 1 patient (0.2%). Although proliferative lesions with atypia were found to increase in number compared with the patients under 40 years, there was no statistical significance found. Ductal in situ carcinoma was demonstrated in 1 patient (1%) younger than 40 years. Although there is no consensus formed for when to send mammoplasty specimens for pathological analysis or how many numbers of tissue sections to submit, we recommend routine pathological analysis of mammoplasty specimens and submitting at least four tissue sections regardless of patients’ age.

Pathologic findings in reduction mammoplasty specimens: a surrogate for the population prevalence of breast cancer and high-risk lesions

Mammoplasty removes random samples of breast tissue from asymptomatic women providing a unique method for evaluating background prevalence of breast pathology in normal population. Our goal was to identify the rate of atypical breast lesions and cancers in women of various ages in the largest mammoplasty cohort reported to date. We analyzed pathologic reports from patients undergoing bilateral mammoplasty, using natural language processing algorithm, verified by human review. Patients with a prior history of breast cancer or atypia were excluded. A total of 4775 patients were deemed eligible. Median age was 40 (range 13-86) and was higher in patients with any incidental finding compared to patients with normal reports (52 vs. 39 years, p = 0.0001). Pathological findings were detected in 7.06% (337) of procedures. Benign high-risk lesions were found in 299 patients (6.26%). Invasive carcinoma and ductal carcinoma in situ were detected in 15 (0.31%) and 23 (0.48%) patients, respectively. The rate of atypias and cancers increased with age. The overall rate of abnormal findings in asymptomatic patients undergoing mammoplasty was 7.06%, increasing with age. As these results are based on random sample of breast tissue, they likely underestimate the prevalence of abnormal findings in asymptomatic women.

Recommendations for Pathologic Evaluation of Reduction Mammoplasty Specimens: A Prospective Study With Systematic Tissue Sampling.

- Breast reduction mammaplasty (RMP) for symptomatic macromastia or correction of asymmetry is performed in more than 100 000 patients per year in the United States. The reported incidence of significant pathologic findings (SPF), that is, carcinoma and atypical hyperplasia, ranges from 0.06% to 12.8%. No standard pathology assessment for RMP exists. - To propose standard sampling for microscopic evaluation in RMP specimens, to evaluate the incidence of occult carcinoma and atypical hyperplasia, and to identify clinical risk factors for SPF in patients undergoing RMP. - All RMP specimens from 2006 to 2013 at a single institution were prospectively examined. After baseline gross and microscopic evaluations, each specimen was subjected to systematic additional sampling. The incidence of SPF was tabulated, and variables such as age, specimen weight, previous history of SPF, and results of preoperative mammogram were examined. Clinical follow-up review was also subsequently undertaken. - A total of 595 patients were evaluated. Significant pathologic findings were present in 9.8% (58 of 595) of patients. No cancer was identified in patients younger than 40 years; the rates of carcinoma were 2.4% (14 of 595) in all patients, 3.6% (14 of 392) in patients aged 40 years or older, and 4.3% (10 of 233) in patients aged 50 years or older. No carcinoma or atypical hyperplasia was identified on preoperative mammogram. Increased sampling was associated with a significantly greater frequency of SPF only in patients aged 40 years or older. - In patients younger than 35 years, gross-only evaluation is sufficient. However, increased sampling may be necessary in patients older than 40 years.

Incidental breast carcinoma in reduction mammoplasty

Aim: The objective of this study was to analyze the incidence and treatment options of occult cancer or atypical lesions found in the histopathological examination of reduction mammoplasty (RM) specimens. The role of preoperative mammography and systematic histopathological examination are discussed.Methods: We performed a retrospective single-center database review of all patients who underwent a RM between January 2005 and December 2014. Preoperative examination, histopathological findings and follow-up were documented.Results: A total of 1045 patients underwent RM, of which 97% were bilateral (1021). All patients received a mammography and routine clinical examination to exclude cancer preoperatively. The overall mean patient age was 40.2 years (14.2–73.4). A total of 19 patients (1.18%) had significant histopathological findings, all of whom were over 40 years of age. There were 4 incidental carcinomas (0.38%), of which 2 were DCIS (0.19%) and 2 invasive ductal carcinomas (0.19%).Conclusions: Incidence of postoperative diagnosis of occult breast cancer in RM specimens remains low, but poses significant therapeutic challenges. While emphasis should lay on preoperative diagnostics, routine histological analysis of RM specimens is recommended.

Image analysis of immune cell patterns in the human mammary gland during the menstrual cycle refines lymphocytic lobulitis

To improve microscopic evaluation of immune cells relevant in breast cancer oncoimmunology, we aim at distinguishing normal infiltration patterns from lymphocytic lobulitis by advanced image analysis. We consider potential immune cell variations due to the menstrual cycle and oral contraceptives in non-neoplastic mammary gland tissue. Lymphocyte and macrophage distributions were analyzed in the anatomical context of the resting mammary gland in immunohistochemically stained digital whole slide images obtained from 53 reduction mammoplasty specimens. Our image analysis workflow included automated regions of interest detection, immune cell recognition, and co-registration of regions of interest. In normal lobular epithelium, seven CD8[Formula: see text] lymphocytes per 100 epithelial cells were present on average and about 70% of this T-lymphocyte population was lined up along the basal cell layer in close proximity to the epithelium. The density of CD8[Formula: see text] T-cell was 1.6 fold higher in the luteal than in the follicular phase in spontaneous menstrual cycles and 1.4 fold increased under the influence of oral contraceptives, and not co-localized with epithelial proliferation. CD4[Formula: see text] T-cells were infrequent. Abundant CD163[Formula: see text] macrophages were widely spread, including the interstitial compartment, with minor variation during the menstrual cycle. Spatial patterns of different immune cell subtypes determine the range of normal, as opposed to inflammatory conditions of the breast tissue microenvironment. Advanced image analysis enables quantification of hormonal effects, refines lymphocytic lobulitis, and shows potential for comprehensive biopsy evaluation in oncoimmunology.

A 3D in vitro model of the human breast duct: a method to unravel myoepithelial-luminal interactions in the progression of breast cancer

Background3D modelling fulfils a critical role in research, allowing for complex cell behaviour and interactions to be studied in physiomimetic conditions. With tissue banks becoming established for a number of cancers, researchers now have access to primary patient cells, providing the perfect building blocks to recreate and interrogate intricate cellular systems in the laboratory. The ducts of the human breast are composed of an inner layer of luminal cells supported by an outer layer of myoepithelial cells. In early-stage ductal carcinoma in situ, cancerous luminal cells are confined to the ductal space by an intact myoepithelial layer. Understanding the relationship between myoepithelial and luminal cells in the development of cancer is critical for the development of new therapies and prognostic markers. This requires the generation of new models that allows for the manipulation of these two cell types in a physiological setting.MethodsUsing access to the Breast Cancer Now Tissue Bank, we isolated pure populations of myoepithelial and luminal cells from human reduction mammoplasty specimens and placed them into 2D culture. These cells were infected with lentiviral particles encoding either fluorescent proteins, to facilitate cell tracking, or an inducible human epidermal growth factor receptor 2 (HER2) expression construct. Myoepithelial and luminal cells were then recombined in collagen gels, and the resulting cellular structures were analysed by confocal microscopy.Results Myoepithelial and luminal cells isolated from reduction mammoplasty specimens can be grown separately in 2D culture and retain their differentiated state. When recombined in collagen gels, these cells reform into physiologically reflective bilayer structures. Inducible expression of HER2 in the luminal compartment, once the bilayer has formed, leads to robust luminal filling, recapitulating ductal carcinoma in situ, and can be blocked with anti-HER2 therapies.ConclusionsThis model allows for the interaction between myoepithelial and luminal cells to be investigated in an in-vitro environment and paves the way to study early events in breast cancer development with the potential to act as a powerful drug discovery platform.

Incidental Findings in Reduction Mammoplasty Specimens in Patients with No Prior History of Breast Cancer. An Analysis of 783 Specimens.

Breast reduction surgery is a common procedure and the rate of incidental findings in the removed specimens varies between 0% and 4.6%. There are no guidelines about pathological evaluation of breast reduction surgery. We reviewed all pathology reports of patients undergoing breast reduction surgery in a single tertiary institution in Brazil from January 2008 to August 2014. Exclusion criteria were a personal history of breast cancer, unclear reason for mastectomy and incomplete data on the pathology report. We considered "relevant findings" flat epithelial atypia, atypical hyperplasia, carcinomas in situ and invasive carcinoma. Of 1672 specimens from breast reduction surgery, 783 met inclusion criteria. Median patient age was 40 (8-77), 91% underwent bilateral mastectomy and 57% of the specimens weighted less than 200g. In 55% of cases, 4 or more paraffin blocks were sampled. There were 40 (5.1%) relevant findings and the most common was atypical lobular hyperplasia (16-2%). There were 3 invasive carcinomas (0.38%). In multivariate analysis, the only variables associated with a higher odds of relevant pathological findings were patient age≥40 (OR 4.73 CI95% 1.98-11.3 p<0.001) and sampling of ≥4 paraffin blocks from each specimen (OR 6.69 95% CI 2.25-19.9 p<0.001). The incidence of pre-malignant and malignant lesions in specimens from breast reduction surgery is around 5%, but this risk is significantly higher for patients older than 40years-old. Sampling at least 4 paraffin blocks from each specimen significantly increases detection rates.

Abstract: Approach to Management Using Evidence Based Medicine: Proliferative Breast Lesions Among Reduction Mammoplasty Specimens

INTRODUCTION: Given the reported lifetime estimate of 1 in 8 women becoming diagnosed with breast carcinoma, it is standard perioperative practice for excised tissue obtained from routine reduction mammoplasty procedures to be sent for pathology review. 1 On average, an estimated 0.2–1.1% of all reduction mammoplasty specimens reviewed by pathology is diagnosed with occult malignancy.2–5 On occasion, atypical proliferative lesion of variable malignancy potential is also reported, which may become an area of concern given the management of such lesions may be unfamiliar to plastic surgeons. We aimed to provide a review of commonly diagnosed proliferative lesions identified in routine reduction mammoplasty specimens and the best supporting evidence for their subsequent management. METHODS: Retrospective literature review using a PubMed search of all English-language articles published between 1990 and 2016 containing the phrases (“reduction mammoplasty”, “breast reduction”, “proliferative”, “atypical”, “hyperplasia”, “ductal”, “epithelial”, “lobular”, “stromal” and “meshchymal”) was completed. A total of 210 publications were generated after initial screening with 10 articles ultimately incorporated after comprehensive review. RESULTS: Commonly encountered proliferative lesions among reduction mammoplasty specimens include pseudoangiomatous stromal hyperplasia (PASH), atypical lobular hyperplasia (ALH), atypical ductal hyperplasia (ADH) and flat epithelial atypia (FEA). PASH and FEA with no concomitant atypical ductal or lobular lesions confers no risk of subsequent malignancy and routine standard of care is recommended. ADH and ALH confer a four-fivefold increased risk of subsequent breast carcinoma with increased risk among high risk individuals.2 For this patient cohort, current management strategies recommend referral to a breast program, biannual clinical exam, yearly mammography with breast MRI, genetic testing for BRCA 1/2 gene mutation with or without chemoprevention in higher risk individuals. CONCLUSION: Our review provides important findings by highlighting the most frequently encountered atypical proliferative lesions among routine reduction mammoplasty specimens as well as current evidence supporting management strategies. DISCLOSURE/FINANCIAL SUPPORT:The authors report no financial disclosure REFERENCES: 1. American Cancer Society. Breast Cancer Facts & Figures 2013–2014. Atlanta: American Cancer Society, Inc. 2013 2. Clark CJ, Whang S, Paige KT. Incidence of precancerous lesions in breast reduction tissue: a pathologic review of 562 consecutive patients. Plast Reconstr Surg. 2009;124(4):1033–1039. doi:10.1097/PRS.0b013e3181b45801. 3. Desouki MM, Li Z, Hameed O, Fadare O, Zhao C. Incidental atypical proliferative lesions in reduction mammoplasty specimens: Analysis of 2498 cases from 2 tertiary women’s health centers. Hum Pathol. 2013;44(9):1877–1881. doi:10.1016/j.humpath.2013.02.015. 4. Pitanguy I, Torres E, Salgado F, Viana GAP. Breast pathology and reduction mammaplasty. Plast Reconstr Surg. 2005;115(3):729–734; discussion 735. doi:10.1097/01.PRS.0000152683.62899.50 5. Slezak S, Bluebond-Langner R. Occult carcinoma in 866 reduction mammaplasties: preserving the choice of lumpectomy. Plast Reconstr Surg. 2011;127(2):525–530. doi:10.1097/PRS.0b013e3181fed5dc.

Prerequisites for histopathological evaluation of reduction mammoplasty specimens: Recommendations based on an audit in a tertiary care hospital

Prerequisites for histopathological evaluation of reduction mammoplasty specimens: Recommendations based on an audit in a tertiary care hospital

Abstract P1-01-17: Integrative pathology: Analysis of cellular multiplex technology to detect proteomic, genomic and DNA data from fine needle aspiration biopsy specimens

Abstract Background: An integrative system capable of detecting proteomic, genomic and DNA content from cell isolates obtained by fine needle aspiration (FNA) biopsy may offer distinct advantages in diagnosing breast cancer and monitoring response to therapy. Cellular Multiplex™ is such a system. An initial pilot study evaluating this technology established a series of variables that could separate normal from cancerous elements using cells obtained from an FNA performed on excised tumors and reduction mammoplasty specimens. In order for the technology to be clinically relevant, it must perform robustly on intact tumors. The current study was therefore undertaken to validate Cellular Multiplex™ on cells obtained by FNA performed on intact tumor at the time of diagnosis. Methods: Patients undergoing lumpectomy requiring either needle or 125I seed localization were identified. FNA was performed on intact tumor (A samples) at the time of radiographic localization prior to lumpectomy and repeated on the excised tumor (B samples). Cells obtained by FNA were placed in a proprietary fixative then hybridized and stained to detect multiple mRNA and protein targets along with DNA content. Estrogen receptor, progesterone receptor and HER2 were included in the panel of targets and compared to the routine clinical pathology report. Cell morphology was assessed by mean corpuscular volume. Samples were analyzed using an EC800 (Sony Biotechnology, San Jose, CA) and the results from matched A and B samples were compared using the Mann-Whitney Wilcoxson Rank Sum test. The study is designed to enroll 50 patients. Here we report an analysis of the first 9 cases. Results: The cell number obtained from the excised tumors were 3-4 times greater (median to median) than obtained from the intact tumor. There was no statistical difference in the expression of the 2 mRNA targets, 8 protein targets, DNA content and cell morphology between the A and B samples. The parameters derived from Cellular Multiplex matched the standard pathologic features reported on the clinical pathology report in 8 of 9 cases. In the one discrepant case, Cellular Multiplexing detected ER positive cells in a case where standard pathologic evaluation with immunohistochemistry reported the tumor to be estrogen receptor negative. Conclusions: This interim analysis demonstrates that the Cellular Multiplex technology is working well using cells obtained by FNA performed on intact tumors with readouts matching those obtained from excised specimens. If confirmed in the remaining patients, these data suggest that this technology will be applicable for the evaluation of intact tumors thereby making it relevant for multiple clinical indications including diagnosis and monitoring response to neoadjuvant therapy. Citation Format: Mittendorf EA, Dogan B, Morgan R, Chargin A, Wu Y, Cornett-Risher S, Shults K. Integrative pathology: Analysis of cellular multiplex technology to detect proteomic, genomic and DNA data from fine needle aspiration biopsy specimens. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-01-17.