Benjamin C. Calhoun

Management of flat epithelial atypia on breast core biopsy may be individualized based on correlation with imaging studies

Flat epithelial atypia of the breast commonly co-exists with atypical ductal hyperplasia, lobular neoplasia, and indolent forms of invasive carcinomas such as tubular carcinoma. Most patients with pure flat epithelial atypia on core biopsy undergo surgical excision to evaluate for carcinoma in the adjacent breast tissue. Studies to date have reported varying upgrade rates with most recommending follow-up excision. These studies have often lacked detailed radiographic correlation, central review by breast pathologists and information regarding the biology of the carcinomas identified upon excision. In this study, we report the frequency of upgrade to invasive carcinoma or ductal carcinoma in situ in excision specimens following a diagnosis of pure flat epithelial atypia on core biopsy. Radiographic correlation is performed for each case and grade/receptor status of detected carcinomas is reported. Seventy-three (73) core biopsies containing pure flat epithelial atypia were identified from our files, meeting inclusion criteria for the study. In the subsequent excision biopsies, five (7%) cases contained invasive carcinoma or ductal carcinoma in situ and seventeen (23%) contained atypical ductal hyperplasia or lobular neoplasia. All of the ductal carcinoma in situ cases with estrogen receptor results were estrogen receptor positive and intermediate grade. The invasive tumors were small (pT1a) hormone receptor-positive, HER2-negative, low-grade invasive ductal or tubular carcinomas with negative sentinel lymph-node biopsies. No upgrades were identified in the 14 patients who had all of their calcifications removed by the stereotactic core biopsy. Our rate of upgrade to carcinoma, once cases with discordant imaging are excluded, is at the lower end of the range reported in the literature. Given the low upgrade rate and indolent nature of the carcinomas associated with flat epithelial atypia, case management may be individualized based on clinical and radiographic findings. Excision may not be necessary for patients without remaining calcifications following core biopsy.

Recommendations for excision following core needle biopsy of the breast: a contemporary evaluation of the literature

Pathologists frequently encounter non‐malignant histological findings in percutaneous core needle biopsies (CNBs). Standards for the management of patients with lesions such as atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ, as well as other benign lesions, are not well defined, and recommendations for surgical biopsy or continued clinical and radiological follow‐up are inconsistent. The frequency with which these lesions are ‘upgraded’ to carcinoma in excision specimens is widely variable in the literature. Many CNB studies lack careful radiological–pathological correlation, clear criteria for excision, and clinical follow‐up for patients on whom excision was not performed. This review of the recent literature emphasizes studies with radiological–pathological correlation, with the goal of developing a contemporary, evidence‐based approach to the management of non‐malignant lesions of the breast diagnosed on CNB. The data supporting an emerging consensus on which lesions may not require excision are highlighted. The management of non‐malignant lesions diagnosed on magnetic resonance imaging‐guided CNB is also discussed.

Predictive markers in breast cancer: An update on ER and HER2 testing and reporting

Gene expression profiling of human tumors has provided a new paradigm for classifying breast carcinomas, predicting response to treatment, and risk of recurrence. Estrogen receptor (ER), human epidermal growth factor 2 (HER2) receptor, and proliferation-related genes are the main drivers of classification in many of the gene expression profiling tests for breast cancer. However, ER, progesterone receptor (PR), and HER2 receptor status remain essential in determining the need and type of adjuvant therapy. These biomarkers are routinely tested for in all invasive breast carcinomas; ER testing is also performed on cases of ductal carcinoma in situ (DCIS). This article will provide an update on current guidelines from the American Society of Clinical Oncologists (ASCO) and the College of American Pathologists (CAP) for ER and HER2 testing by immunohistochemistry (IHC) and in situ hybridization (ISH). The populations to be tested, antibody selection, criteria for interpretation, and reporting are discussed. The molecular alterations that correlate with IHC results, alternative methods of testing, and the current approach to complex aspects of HER2 testing, including heterogeneity and polysomy, also are summarized.

Mitigating Overdiagnosis and Overtreatment in Breast Cancer: What Is the Role of the Pathologist?

After decades of experience with breast cancer screening programs in the United States and other countries, recent attention has focused on balancing the benefits and harms of screening for breast cancer. In a Viewpoint article entitled ‘‘Overdiagnosis and Overtreatment in Cancer: An Opportunity for Improvement’’ in the August 28, 2013, issue of the Journal of the American Medical Association (JAMA), Esserman et al summarized recommendations from a working group charged with improving the current approach to cancer screening and prevention. The JAMA Viewpoint is generating considerable debate in the medical community and was widely reported in the national media. The working group evolved out of a National Cancer Institute meeting convened to evaluate the problem of ‘‘overdiagnosis’’ or overdetection, most often defined as the detection of tumors by screening that, if left unattended, would not become clinically significant or cause death. The treatment of all such screen-detected tumors potentially results in overtreatment of a subset of patients whose tumors may be indolent, unlikely to affect their well-being or mortality. For some tumors, including breast cancer, the significant increase in the detection of early-stage disease, in the absence of a commensurate decline in more advanced disease, may lead to overtreatment of more patients. The working group offered 5 recommendations: (1) recognize that overdiagnosis is common and more frequent with cancer screening, (2) change cancer terminology based on companion diagnostics, (3) create observational registries for low malignant potential lesions, (4) mitigate overdiagnosis, and (5) expand the concept of how to approach cancer progression. This editorial will review key ideas in the overdiagnosis and overtreatment debate from the perspective of practicing pathologists. We will highlight 3 areas in which we believe pathologists can and should participate: the classification of potential precursor lesions for breast cancer, clear communication of their cancer risk implications, and participation in multidisciplinary studies to better define the risk of recurrence and progression for those lesions in individual patients.

Breast cancer risk associated with atypical hyperplasia and lobular carcinoma in situ initially diagnosed on core-needle biopsy

Breast cancer risk estimates for atypical lesions are based primarily on case‐control studies of patients with open biopsies. The authors report the cumulative breast cancer incidence after a core biopsy diagnosis of atypical hyperplasia (ductal or lobular) or lobular carcinoma in situ.

Breast tissue, oral and urinary microbiomes in breast cancer

It has long been proposed that the gut microbiome contributes to breast carcinogenesis by modifying systemic estrogen levels. This is often cited as a possible mechanism linking breast cancer and high-fat, low-fiber diets as well as antibiotic exposure, associations previously identified in population-based studies. More recently, a distinct microbiome has been identified within breast milk and tissue, but few studies have characterized differences in the breast tissue microbiota of patients with and without cancer, and none have investigated distant body-site microbiomes outside of the gut. We hypothesize that cancerous breast tissue is associated with a microbiomic profile distinct from that of benign breast tissue, and that microbiomes of more distant sites, the oral cavity and urinary tract, will reflect dysbiosis as well. Fifty-seven women with invasive breast cancer undergoing mastectomy and 21 healthy women undergoing cosmetic breast surgery were enrolled. The bacterial 16S rRNA gene was amplified from urine, oral rinse and surgically collected breast tissue, sequenced, and processed through a QIIME-based bioinformatics pipeline. Cancer patient breast tissue microbiomes clustered significantly differently from non-cancer patients (p=0.03), largely driven by decreased relative abundance of Methylobacterium in cancer patients (median 0.10 vs. 0.24, p=0.03). There were no significant differences in oral rinse samples. Differences in urinary microbiomes were largely explained by menopausal status, with peri/postmenopausal women showing decreased levels of Lactobacillus. Independent of menopausal status, however, cancer patients had increased levels of gram-positive organisms including Corynebacterium (p<0.01), Staphylococcus (p=0.02), Actinomyces (p<0.01), and Propionibacteriaceae (p<0.01). Our observations suggest that the local breast microbiota differ in patients with and without breast cancer. Cancer patient urinary microbiomes were characterized by increased levels of gram-positive organisms in this study, but need to be further studied in larger cohorts.

Radial scars diagnosed on breast core biopsy: Frequency of atypia and carcinoma on excision and implications for management

AIMS The risk of finding carcinoma in excisions following a core needle biopsy diagnosis of radial scar is not well defined and clinical management is variable. The aim of this study is to determine the frequency of high-risk lesions, ductal carcinoma in situ, and invasive carcinoma in excisions following a core biopsy diagnosis of radial scar. METHODS AND RESULTS Dedicated breast pathologists and radiologists correlated the histologic and radiologic findings and categorized radial scars as the target lesion or an incidental finding. High-risk lesions were defined as atypical hyperplasia or classical lobular carcinoma in situ. Of the 79 radial scars identified over a 14-year period, 22 were associated with atypia or carcinoma in the core biopsy. Thirty-seven (37) of the 57 benign radial scars underwent excision with benign findings in 30 (81%), high-risk lesions in six (16%), and flat epithelial atypia in one (3%). There were no upgrades to carcinoma. One patient with a benign radial scar developed a 3-mm focus of intermediate-grade estrogen receptor-positive ductal carcinoma in situ in the same quadrant of the ipsilateral breast 72 months after excision. One patient with an incidental un-excised benign radial scar was diagnosed with ductal carcinoma in situ at a separate site of suspicious calcifications. CONCLUSIONS In this series, none of the benign radial scars was upgraded to carcinoma. Radial scar was the targeted lesion in all cases with high-risk lesions on excision. Surgical excision may not be mandatory for patients with benign incidental radial scars on core biopsy.

Atypical apocrine adenosis diagnosed on breast core biopsy: implications for management

Apocrine adenosis (AA) and atypical apocrine adenosis (AAA) are uncommon findings in breast biopsies that may be misinterpreted as carcinoma. The data from long-term follow up studies of open biopsies suggest that AAA is not a high-risk or precursor lesion. The clinical significance and risk implications of AAA diagnosed on core biopsy are not well established. The goal of this study was to determine the frequency of carcinoma in excision specimens after a core biopsy diagnosis of AA or AAA. We identified 34 core biopsies of AA (22) and AAA (12) performed between 1996 and 2014. The mean age at diagnosis was 60 years. The most common indications for core biopsy were calcifications (11), a mass or density (18), and a mass or density with calcifications (3). Two cases were detected on magnetic resonance imaging (MRI) studies. Available pathology reports and slides were reviewed, and surgical excision findings were correlated with core biopsy diagnoses. Of the core biopsies with AA or AAA, 7 also contained atypical ductal or lobular hyperplasia (AH) and 4 contained ductal carcinoma in situ or invasive carcinoma. In the absence of coexisting AH or carcinoma in the initial core biopsy specimen, none of the surgical excision specimens after a diagnosis of AA (2) or AAA (7) contained ductal carcinoma in situ or invasive carcinoma. AAA by itself is an uncommon core biopsy diagnosis that may not require surgical excision.

Mucocele-like lesions diagnosed on breast core biopsy: Low risk of upgrade and subsequent carcinoma

Mucocele‐like lesions of the breast diagnosed on core biopsy are usually excised to exclude the possibility of partial sampling of an invasive mucinous carcinoma. The goal of this study was to correlate the pathologic and radiologic features of mucocele‐like lesions to determine if excision is mandatory. Over a 16 year period we identified 32 patients with mucocele‐like lesions diagnosed on 27 (84%) stereotactic and 5 (16%) ultrasound‐guided core biopsies. The indications for core biopsy were: calcifications in 24 (75%), a mass in 7 (22%), and a mass with calcifications in 1 (3%). There were 22 (69%) mucocele‐like lesions without atypia and 10 (31%) with atypical ductal hyperplasia or detached groups of atypical cells. Of the 22 mucocele‐like lesions without atypia, 19 (86%) were excised: 15/19 (79%) were benign, 3/19 (16%) had atypical ductal hyperplasia and 1/19 (5%) had ductal carcinoma in situ. None of the patients with mucocele‐like lesions without atypia were upgraded to invasive carcinoma. The single patient who was upgraded to low‐grade ductal carcinoma in situ had a history of ductal carcinoma in situ in the same breast. Of the 10 patients with mucocele‐like lesions with atypia, 9 (90%) were excised: 5/9 (56%) were benign, 1/9 (11%) had atypical ductal hyperplasia and 3/9 (33%) had invasive carcinoma. Of the patients with mucocele‐like lesions with atypia who were upgraded to invasive carcinoma, one had a BIRADS 5 mass and discordant pathology and one had a history of Hodgkin lymphoma and mantle radiation. There were 24 patients with mucocele‐like lesions with or without atypia who were not upgraded on excision, and none developed breast cancer after a median of 51 months (range 7‐192). These findings indicate that mucocele‐like lesions without atypia are unlikely to be upgraded on excision and are associated with a low risk for the subsequent development of carcinoma.

Impact of an alternative chromosome 17 probe and the 2013 American Society of Clinical Oncology and College of American Pathologists guidelines on fluorescence in situ hybridization for the determination of HER2 gene amplification in breast cancer.

The dual‐probe fluorescence in situ hybridization (FISH) assay for human epidermal growth factor receptor 2 (HER2) gene amplification in breast cancer provides an HER2:CEP17 (centromere enumeration probe for chromosome 17) ratio. Copy number alteration (CNA) in CEP17 may skew this ratio. The authors analyzed the impact of the 2013 American Society of Oncology/College of American Pathologists (ASCO/CAP) guidelines and an alternative chromosome 17 probe on HER2 status in tumor specimens with CEP17 CNA.