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Fibroepithelial lesions with cellular stroma are frequently termed cellular fibroadenomas although criteria for distinguishing them from a phyllodes tumor are vague and subjective. However, the clinical implications and surgical management for these 2 lesions may be different. We randomly selected 21 cases of fibroepithelial lesions sent in consultation to the senior author that were challenging to classify as cellular fibroadenoma or phyllodes tumor. One to 2 representative slides of each case along with patient age were sent to 10 pathologists who specialize in breast pathology. The World Health Organization criteria for phyllodes tumors and a diagnosis form were included with the study set. For the purposes of data reporting, fibroadenoma and cellular fibroadenoma are considered together. In only 2 cases was there uniform agreement as to whether the tumor represented a fibroadenoma or phyllodes tumor. Of the remaining 19 cases, if the diagnoses of fibroadenoma and benign phyllodes tumor were combined and separated from borderline and malignant phyllodes tumors, there was 100% agreement in 53% of cases and 90% agreement in 79% of cases. This study highlights the difficulty that exists in distinguishing some cellular fibroadenomas from phyllodes tumors even for pathologists who specialize in breast pathology. However, there appears to be considerable agreement when cellular fibroadenomas and benign phyllodes tumors are distinguished from borderline and malignant phyllodes tumors. Further studies are needed to determine if there is a clinically significant difference between cellular fibroadenomas and benign phyllodes tumors and how to better distinguish them from borderline and malignant phyllodes tumors., (© The Author(s) 2014.)

Background: The role and clinical value of ERβ1 expression is controversial and recent data demonstrates that many ERβ antibodies are insensitive and/or non-specific. Therefore, we sought to comprehensively characterize ERβ1 expression across all sub-types of breast cancer using a validated antibody and determine the roles of this receptor in mediating response to multiple forms of endocrine therapy both in the presence and absence of ERα expression., Methods: Nuclear and cytoplasmic expression patterns of ERβ1 were analyzed in three patient cohorts, including a retrospective analysis of a prospective adjuvant tamoxifen study and a triple negative breast cancer cohort. To investigate the utility of therapeutically targeting ERβ1, we generated multiple ERβ1 expressing cell model systems and determined their proliferative responses following anti-estrogenic or ERβ-specific agonist exposure., Results: Nuclear ERβ1 was shown to be expressed across all major sub-types of breast cancer, including 25% of triple negative breast cancers and 33% of ER-positive tumors, and was associated with significantly improved outcomes in ERα-positive tamoxifen-treated patients. In agreement with these observations, ERβ1 expression sensitized ERα-positive breast cancer cells to the anti-cancer effects of selective estrogen receptor modulators (SERMs). However, in the absence of ERα expression, ERβ-specific agonists potently inhibited cell proliferation rates while anti-estrogenic therapies were ineffective., Conclusions: Using a validated antibody, we have confirmed that nuclear ERβ1 expression is commonly present in breast cancer and is prognostic in tamoxifen-treated patients. Using multiple breast cancer cell lines, ERβ appears to be a novel therapeutic target. However, the efficacy of SERMs and ERβ-specific agonists differ as a function of ERα expression.

Objective: The purpose of this study was to determine the proportion of invasive lobular carcinomas with increased sonographic echogenicity., Materials and Methods: A retrospective review of mammographic and sonographic findings included cases of pure invasive lobular carcinoma with available images from January 1998 to June 2010. We assessed ultrasound images for the presence of a mass, internal echogenicity, margin characteristics, and attenuation effects. In hyperechoic tumors, more than 90% of the mass had increased echogenicity compared with surrounding fat. In heterogeneously echogenic tumors, the echogenic component constituted 20-90% of the tumor. Findings at mammography, MRI, and surgery were correlated with sonographic findings. A breast pathologist reviewed histologic findings and confirmed the diagnosis of pure invasive lobular carcinoma., Results: Of 509 invasive lobular carcinomas, 27 (5%) were hyperechoic, of which 13 (48%) were associated with posterior acoustic shadowing. Heterogeneously echogenic cancer was seen in 57 (11%) cases. The most common sonographic finding was a hypoechoic, irregular mass with or without posterior shadowing (n = 323; 63%). In 66 (13%) lesions, focal shadowing was seen without a discrete mass. Fourteen (3%) lesions were isoechoic with respect to surrounding normal adipose tissue without acoustic shadowing. Twenty-two (4%) of the malignant tumors were not identified sonographically. Of these, 15 (68%) had mammographic abnormalities, one (5%) was seen at MRI, and six (27%) presented as palpable masses that were surgically excised., Conclusion: Pure invasive lobular carcinomas can present as a hyperechoic mass or with substantial hyperechoic component. All sonographic lesion characteristics should be evaluated and biopsy recommended when there are suspicious features, even in a lesion that is predominantly hyperechoic.

Background: The purpose of this study was to determine whether surgical excision of benign solitary intraductal papillomas (BSIP) diagnosed by core needle biopsy (CNBx) without an associated high-risk lesion and concordant with imaging is justified., Methods: A review of all papillary lesions diagnosed by CNBx from January 2003 to June 2010 was performed. Available histologic and radiologic materials were evaluated in a blinded fashion by three pathologists and three dedicated breast radiologists, respectively, to assess for concordance. The papillary lesions were designated as benign, atypical, or malignant. There were 16 BSIPs excluded because of an adjacent high-risk lesion or same-quadrant ipsilateral cancer. All immediate and delayed excisional specimens were reviewed. Clinical and radiologic data were recorded., Results: A total of 299 papillary lesions diagnosed on CNBx and concordant with imaging were identified. Of these, 240 (80 %) were classified as benign, 49 (16 %) atypical, and 10 (3 %) malignant. After exclusions, 77 of 224 women in our study cohort (34 %) underwent surgical excision with no atypical or malignant upgrades. Of the remaining 147 women diagnosed with a BSIP on CNBx, 47 (32 %) were lost to follow-up and 100 (68 %) were observed. All 100 observed patients had stable imaging findings at follow-up (4.8-93.8 months, mean 36.0 months)., Conclusions: The likelihood of diagnosing atypia or malignancy after surgical excision of a BSIP diagnosed on CNBx without associated high-risk lesion or ipsilateral quadrant malignancy is extremely low. For this distinct subset of patients with a BSIP, these data justify close imaging follow-up, rather than surgical excision.

Radioactive seed localization (RSL) is an increasingly utilized and effective approach to surgical excision of radiographically identified lesions in the breast. This approach has been reported to be at least as convenient to the patient, radiologist, and surgeon as the standard wire localized approach but with the considerable added benefit of a lower positive margin rate in some studies. To date, there is little information in the published medical literature concerning the optimal handling of these specimens in the pathology laboratory. The US Nuclear Regulatory Commission and its Agreement States oversee the use of radioactive materials in clinical practice and provide guidelines for the performance of RSL procedures, including the safe handling of radioactive seeds. The RSL procedure involves multiple departments, and a robust process should be in place to ensure appropriate accountability, seed tracking, and minimal radiation exposure to staff. This article describes how to properly and safely handle RSL breast specimens, including regulation requirements, specimen labeling and receipt, specimen dissection, protective wear, and seed retrieval, transport, and disposal.

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

We present the case of an 83 year old woman with a cardiac pacemaker located close in distance to a subsequently diagnosed invasive ductal carcinoma of the left breast. Short range intraoperative radiotherapy was given following wide local excision and sentinel node biopsy. The challenges of using ionising radiation with pacemakers is also discussed.

Background: Few studies have examined differences between rural and urban women in mammography barriers, knowledge, and experiences. Exploring differences can help inform tailored interventions., Methods: Women, aged ≥40, who had not been screened in the past 2 years were recruited from eight federally qualified health centers across Louisiana. They were given a structured interview assessing mammography knowledge, beliefs, barriers, experiences, and literacy., Results: Of the 1189 patients who participated, 65.0% were African American, 61.6% were rural, and 44.0% had low literacy. Contrary to guidelines, most believed mammography should be done annually (74.3%) before age 40 (70.5%). Compared to urban women, rural participants were more likely to believe mammography will find small breast lumps early (34.4% vs. 6.5%, p<0.0001) and strongly disagree that mammography is embarrassing (14.6% vs. 8.4%, p=0.0002) or that they are afraid of finding something wrong (21.2% vs.12.3%, p=0.007). Rural women were more likely to report a physician recommendation for mammography (84.3% vs. 76.5%, p=0.006), but they were less likely to have received education (57.2% vs. 63.6%, p=0.06) or to have ever had a mammogram (74.8% vs. 78.1%, p=0.007). In multivariate analyses controlling for race, literacy, and age, all rural/urban differences remained significant, except for receipt of a mammogram., Conclusions: Most participants were unclear about when they should begin mammography. Rural participants reported stronger positive beliefs, higher self-efficacy, fewer barriers, and having a physician recommendation for mammography but were less likely to receive education or screening.

Background: The development of predictive biomarkers for IGF targeted anti-cancer therapeutics remains a critical unmet need. The insulin receptor A isoform (InsR-A) has been identified as a possible biomarker candidate but quantification of InsR-A in widely available formalin fixed paraffin embedded (FFPE) tissues is complicated by its similarities with the metabolic signaling insulin receptor isoform B (InsR-B). In the present study, qPCR based assays specific for InsR-A, InsR-B and IGF-1R were developed for use in FFPE tissues and tested for feasible use in clinical archived FFPE estrogen receptor (ER)+and ER- breast cancer tumors., Design: FFPE compatible primer sets were designed with amplicon sizes of less than 60 base pairs and validated for target specificity, assay repeatability and amplification efficiency. FFPE tumors from ER+ (n=83) and ER-(n=64) primary untreated breast cancers, and ER+ hormone refractory (HR ER+) (n=61) breast cancers were identified for feasibility testing. The feasible use of InsR-A and InsR-B qPCRs were tested using all tumor groups and the feasibility of IGF-1R qPCR was determined using HR ER+ tumors., Results: All qPCR assays were highly reproducible with amplification efficiencies between 96-104% over a 6 log range with limits of detection of 4 or 5 copies per reaction. Greater than 90% of samples were successfully amplified using InsR-A, InsR-B or IGF-1R qPCR primer sets and greater than 88% of samples tested amplified both InsR isoforms or both isoforms and IGF-1R. InsR-A was the predominant isoform in 82% ER+, 68% ER- and 100% HR ER+ breast cancer. Exploratory analyses demonstrated significantly more InsR-A expression in ER+ and HR ER+ groups compared to InsR-B (ER+ p<0.05, HR ER+ p<0.0005) and both groups had greater InsR-A expression when compared to ER- tumors (ER+ p<0.0005, HR ER+ p<0.05). IGF-1R expression of HR ER+ tumors was lower than InsR-A (p<0.0005) but higher than InsR-B (p<0.0005). The InsR-B expression of HR ER+ tumors was significantly reduced compared other tumor subgroups (ER+ and ER-, p<0.0005) and lead to a significant elevation of HR ER+ InsR-A: InsR-B ratios (ER+ and ER-, p<0.0005)., Conclusions: The validated, highly sensitive InsR-A and InsR-B qPCR based assays presented here are the first to demonstrate the feasible amplification of InsR isoforms in FFPE tissues. Quantification data generated from this feasibility study indicating InsR-A is more predominant than InsR-B in breast cancer support the use of these assays for further investigation of InsR-A and InsR-B as predictive biomarkers for IGF targeted therapeutics., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: In vivo dosimetry provides an independent check of delivered dose and gives confidence in the introduction or consistency of radiotherapy techniques. Single-fraction intraoperative radiotherapy of the breast can be performed with the Intrabeam compact, mobile 50 kV x-ray source (Carl Zeiss Surgical, Oberkochen, Germany). Thermoluminescent dosimeters (TLDs) can be used to estimate skin doses during these treatments., Methods and Materials: Measurements of skin doses were taken using TLDs for 72 patients over 3 years of clinical treatments. Phantom studies were also undertaken to assess the uncertainties resulting from changes in beam quality and backscatter conditions in vivo., Results: The mean measured skin dose was 2.9 ± 1.6 Gy, with 11% of readings higher than the prescription dose of 6 Gy, but none of these patients showed increased complications. Uncertainties due to beam hardening and backscatter reduction were small compared with overall accuracy., Conclusions: TLDs are a useful and effective method to measure in vivo skin doses in intraoperative radiotherapy and are recommended for the initial validation or any modification to the delivery of this technique. They are also an effective tool to show consistent and safe delivery on a more frequent basis or to determine doses to other critical structures as required., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The role of estrogen receptor alpha (ERα) in breast cancer has been studied extensively, and its protein expression is prognostic and a primary determinant of endocrine sensitivity. However, much less is known about the role of ERβ and its relevance remains unclear due to the publication of conflicting reports. Here, we provide evidence that much of this controversy may be explained by variability in antibody sensitivity and specificity and describe the development, characterization, and potential applications of a novel monoclonal antibody targeting full-length human ERβ and its splice variant forms. Specifically, we demonstrate that a number of commercially available ERβ antibodies are insensitive for ERβ and exhibit significant cross-reaction with ERα. However, our newly developed MC10 ERβ antibody is shown to be highly specific and sensitive for detection of full-length ERβ and its variant forms. Strong and variable staining patterns for endogenous levels of ERβ protein were detected in normal human tissues and breast tumors using the MC10 antibody. Importantly, ERβ was shown to be expressed in a limited cohort of both ERα positive and ERα negative breast tumors. Taken together, these data demonstrate that the use of poorly validated ERβ antibodies is likely to explain much of the controversy in the field with regard to the biological relevance of ERβ in breast cancer. The use of the MC10 antibody, in combination with highly specific antibodies targeting only full-length ERβ, is likely to provide additional discriminatory features in breast cancers that may be useful in predicting response to therapy., (Copyright © 2011 Wiley Periodicals, Inc.)

Mammographic density is a strong risk factor for breast cancer but its underlying biology in healthy women is not well-defined. Using a novel collection of core biopsies from mammographically dense versus non-dense regions of the breasts of healthy women, we examined histologic and molecular differences between these two tissue types. Eligible participants were 40 + years, had a screening mammogram and no prior breast cancer or current endocrine therapy. Mammograms were used to identify dense and non-dense regions and ultrasound-guided core biopsies were performed to obtain tissue from these regions. Quantitative assessment of epithelium, stroma, and fat was performed on dense and non-dense cores. Molecular markers including Ki-67, estrogen receptor (ER) and progesterone receptor (PR) were also assessed for participants who had >0% epithelial area in both dense and non-dense tissue. Signed rank test was used to assess within woman differences in epithelium, stroma and fat between dense and non-dense tissue. Differences in molecular markers (Ki-67, ER, and PR) were analyzed using generalized linear models, adjusting for total epithelial area. Fifty-nine women, mean age 51 years (range: 40-82), were eligible for analyses. Dense tissue was comprised of greater mean areas of epithelium and stroma (1.1 and 9.2 mm(2) more, respectively) but less fat (6.0 mm(2) less) than non-dense tissue. There were no statistically significant differences in relative expression of Ki-67 (P = 0.82), ER (P = 0.09), or PR (P = 0.96) between dense and non-dense tissue. Consistent with prior reports, we found that mammographically dense areas of the breast differ histologically from non-dense areas, reflected in greater proportions of epithelium and stroma and lesser proportions of fat in the dense compared to non-dense breast tissue. Studies of both epithelial and stromal components are important in understanding the association between mammographic density and breast cancer risk.

Background: Use of nipple-sparing mastectomy (NSM) is increasing. We sought to look at the role of NSM in BRCA mutation carriers., Methods: Tissue from women with a BRCA1 or BRCA2 mutation who underwent mastectomy between March 1987 and June 2009 at a single institution was reviewed. The entire nipple-areolar complex (NAC) was excised and histologically evaluated. The presence of terminal duct lobular units (TDLUs) and premalignant or malignant lesions in the NAC was noted., Results: Sixty-two NACs from 33 women (25 BRCA1, 8 BRCA2) were studied. TDLUs were present in 15 (24%) NAC specimens. No evidence of atypical hyperplasia, carcinoma in situ, or invasive carcinoma was found in any of the 33 prophylactic mastectomy specimens. Among the 29 breasts with cancer and available tissue, 2 (7%) had malignant findings and 1 (3%) had atypia in the NAC. One woman who underwent bilateral mastectomy for bilateral invasive carcinoma had one nipple with tumor within lymphatics, and her contralateral nipple had atypical lobular hyperplasia. A second woman had ductal carcinoma in situ involving a single major lactiferous duct., Conclusions: The probability of nipple involvement by premalignant or malignant lesions in the NAC of BRCA mutation carriers is low at time of prophylactic mastectomy, but higher (10%) in women undergoing therapeutic mastectomy. NSM may be appropriate and oncologically safe for selected women with BRCA mutations. However, 24% of NACs contained TDLUs, with only 8% found in the nipple papilla; the significance of this for long-term risk is unknown.

Aims: The aim of this study was to review the clinicopathological characteristics of neuroendocrine tumours (NETs) metastasizing to the breast, in order to identify features that could be useful in distinguishing these metastatic lesions from primary breast neoplasms., Methods and Results: Eighteen metastatic NETs in the breast were identified from two large hospitals over a 15-year period. Eleven (62%) tumours originated in the gastrointestinal tract, 5 (28%) originated in the lung, and the other two were of indeterminate origin. Eight (44%) cases were initially misdiagnosed as primary mammary carcinomas. In retrospect, all metastatic tumours exhibited architectural and cytological features that would suggest neuroendocrine differentiation. Immunohistochemistry can further aid in the distinction between metastatic neuroendocrine and primary mammary carcinoma. All 11 tumours from the gastrointestinal tract expressed CDX-2, 3 (60%) of five tumours from the lung expressed thyroid transcription factor-1, and only 2 (11%) of 18 showed weak oestrogen receptor positivity. Additionally, unlike primary carcinomas, the majority (82%) of metastatic NETs were negative for cytokeratin 7, and all were negative for gross cystic disease fluid protein 15 and mammoglobin., Conclusions: There is a high propensity for metastatic NETs to mimic primary breast carcinomas. Careful attention to cytological and architectural features can help to identify cases that require further immunophenotypic workup with a panel of tissue-specific antibodies. However, clinical history is paramount for optimal diagnosis., (2011 Blackwell Publishing Limited.)

The objective of this study was to describe the imaging findings of carcinoid tumors metastatic to the breast, with pathologic and clinical correlations. We searched our surgical database for cases of pathologically proven carcinoid tumors metastatic to the breast from October 1, 2000, to May 31, 2010. Of the approximate 10,000 breast biopsies identified, 7000 had malignant findings. Ten cases of metastatic carcinoid (0.1% of all malignancies), all with imaging studies available for review, were included in the study. All patients were women and had their primary carcinoid in the gastrointestinal tract (n=9) or lung (n = 1). One patient presented with a palpable breast mass and no history of carcinoid tumor; an ileal carcinoid was discovered after the pathologic diagnosis of metastatic carcinoid was established. In the breast, tumors presented as solitary lesions in half the cases. Metastases to the breast typically presented as circumscribed masses mammographically and as hypoechoic circumscribed masses ultrasonographically; some showed increased through-transmission and increased vascularity with color Doppler evaluation. Five patients had octreotide scans; of these, 4 had increased focal activity in the region of metastasis within the breast. Six patients underwent computed tomography. Without contrast, nodular masses were observed; with contrast, the masses showed rapid enhancement during arterial phase imaging. Magnetic resonance imaging (n = 4) also showed rapid enhancement and washout kinetics after contrast administration. Recognition of carcinoid metastases to the breast in patients with known or occult primary carcinoid tumors is important to avoid unnecessary treatment for primary breast cancer.

Estrogen receptor (ER) is expressed in normal and malignant breast epithelium, and expression levels have been found to increase with age in normal breast epithelium but not in atypical hyperplasia (AH) and carcinoma in situ. Here we assess ER expression in AH and its association with later breast cancer. ER expression was assessed immunohistochemically in archival sections from 246 women with AH who had open benign breast biopsy from 1967 to 1991. The ACIS III (Dako) was utilized to calculate ER expression in all atypical foci. Using multivariate linear regression, we examined associations of ER expression with age at biopsy, indication for biopsy, type of atypia, number of atypical foci, involution status, and family history. Breast cancer risk across levels of ER expression was also assessed compared with the Iowa SEER control population. Among 246 women, 87 (35%) had atypical ductal hyperplasia (ADH), 141 (57%) had atypical lobular hyperplasia (ALH), and 18 (7%) had both. Forty-nine (20%) developed breast cancer (median follow-up of 14.4 years). Multivariate analysis indicated that type of atypia and age at diagnosis were significantly associated with ER percent staining and intensity (P < 0.05). ER expression was increased in women with ADH and/or those over age 55. ER expression did not significantly impact breast cancer risk in patients diagnosed with atypia. We found increasing ER expression in AH with increasing age. ER expression in AH does not further discriminate breast cancer risk in women with atypia.

Mammographic breast density (MBD) is one of the strongest risk factors for breast cancer. Unfortunately, the biologic basis underlying this association is unknown. This study compared aromatase expression or immunoreactivity (IR) in core biopsies from mammographically dense versus non-dense regions of the breast to examine whether estrogen synthesis in the breast is associated with MBD and one possible mechanism through which MBD may influence breast cancer. Eligible participants were 40+ years, had a screening mammogram with visible MBD and no prior cancer or current endocrine therapy. Mammograms were used to identify dense and non-dense regions and ultrasound-guided core biopsies were performed to obtain tissue from these regions. Immunostaining for aromatase employed the streptavidin-biotin amplification method and #677 mouse monoclonal antibody. Aromatase IR was scored in terms of extent and intensity of staining for each cell type (stroma, epithelium, adipocytes) on histologic sections. A modified histological H-score provided quantitation of aromatase IR in each cell type and overall. Repeated measure analyses evaluated average differences (β(H)) in H-score in dense versus non-dense tissue within and across cell types. Forty-nine women with mean age 50 years (range: 40-82), participated. Aromatase IR was increased in dense (vs. non-dense) tissue in both the stroma (β(H) = 0.58) and epithelium (β(H) = 0.12) (P < 0.01). Adipocytes from non-dense tissue, however, had a greater IR compared to those from dense tissue (β(H) = -0.24, P < 0.01). An overall H-score which integrated results from all cell types demonstrated that aromatase IR was twice as great for dense (mean H-score = 0.90, SD = 0.53) versus non-dense (mean H-score = 0.45, SD = 0.39) breast tissue (β(H) = 0.45; P < 0.001). Overall, aromatase IR was greater for mammographically dense versus non-dense tissue and may partly explain how MBD influences breast cancer.

Background: In breast cancer, a direct relationship exists between prognosis and the number of lymph nodes involved with metastatic disease. This study was undertaken to determine whether metastatic disease confined to the sentinel lymph nodes (SLN) has better prognosis than metastatic disease spread to non-SLNs, regardless of the number of nodes involved., Methods: The study group consisted of 449 breast cancer patients with positive axillary SLN who underwent regional nodal dissection. Cox proportional-hazard regression models were used to assess the association of the number of positive SLNs and non-SLNs with overall survival (OS) and disease-free survival (DFS)., Results: In patients with disease confined to the SLNs, as the number of positive SLNs increased the OS and DFS remained the same. Once disease was present beyond the SLN, both DFS and OS were negatively impacted. On multivariate analysis non-SLN status remained an independent predictor of OS. A direct comparison was performed on the subset of patients with two positive lymph nodes. Group 1 had all disease confined to the SLNs (two positive SLNs), and group 2 had non-SLN disease (one positive SLN and one positive non-SLN). Despite an identical number of positive nodes, the OS rates were significantly worse in the group with disease present in a non-SLN (P = 0.004)., Conclusion: The number of nodes involved with metastatic disease does not impact OS and DFS if all disease is confined to the SLNs. Non-SLN involvement negatively influences OS and DFS independent of the number of positive nodes.

Purpose: The Oncotype DX assay predicts likelihood of distant recurrence and improves patient selection for adjuvant chemotherapy in estrogen receptor-positive (ER-positive) early stage breast cancer. This study has two primary endpoints: to evaluate the impact of Oncotype DX recurrence scores (RS) on chemotherapy recommendations and to compare the estimated recurrence risk predicted by breast oncology specialists to RS., Methods: One hundred fifty-four patients with ER-positive early stage breast cancer and available RS results were selected. Clinicopathologic data were provided to four surgeons, four medical oncologists, and four pathologists. Participants were asked to estimate recurrence risk category and offer their chemotherapy recommendations initially without and later with knowledge of RS results. The three most important clinicopathologic features guiding their recommendations were requested., Results: Ninety-five (61.7%), 45 (29.2%), and 14 (9.1%) tumors were low, intermediate, and high risk by RS, respectively. RS significantly correlated with tumor grade, mitotic activity, lymphovascular invasion, hormone receptor, and HER2/neu status. Estimated recurrence risk by participants agreed with RS in 54.2% ± 2.3% of cases. Without and with knowledge of RS, 82.3% ± 1.3% and 69.0% ± 6.9% of patients may be overtreated, respectively (p = 0.0322). Inclusion of RS data resulted in a 24.9% change in treatment recommendations. There was no significant difference in recommendations between groups of participants., Conclusions: Breast oncology specialists tended to overestimate the risk of tumor recurrence compared with RS. RS provides useful information that improves patient selection for chemotherapy and changes treatment recommendations in approximately 25% of cases.

Background: Half of all breast cancers are early stage, lymph node negative, and hormone receptor positive. A 21-gene (Oncotype DX®; Genomic Health, Inc., Redwood City, CA) recurrence score (RS) is prognostic for recurrence and predictive of chemotherapy benefit. We explored the ability of oncologists to predict the RS using standard prognostic criteria., Methods: Standard demographic and tumor prognostic criteria were obtained from patients with an available RS. Two academic pathologists provided tumor grade, histologic type, and hormone receptor status. Six academic oncologists predicted the RS category (low, intermediate, or high) and provided a recommendation for therapy. The oncologists were then given the actual RS and provided recommendations for therapy. Analysis for agreement was performed., Results: Thirty-one cases, including nine additional cases with variant pathology reads, were presented. There was substantial agreement in oncologists' ability to discriminate between true low or true intermediate and true high (κ = 0.75; p < .0001). Predictions between low and intermediate were not consistent. The most common discrepancies were predictions of a low RS risk when cases were true intermediate and predictions of an intermediate RS risk when cases were true low. The actual RS resulted in a change in the treatment recommendations in 19% of cases. Of the 186 scenarios and six oncologists in aggregate, five fewer chemotherapy recommendations resulted with the actual RS., Conclusions: Oncologists are able to differentiate between a low or intermediate RS and a high RS using standard prognostic criteria. However, provision of the actual RS changed the treatment recommendations in nearly 20% of cases, suggesting that the RS may reduce chemotherapy use. This effect was observed in particular in intermediate-risk cases. Prospective clinical trials are necessary to determine whether decisions based on the RS change outcomes.

Objective: The purpose of this study was to assess the accuracy of 5 sonographic features in the prediction of extranodal extension (ENE) in axillary lymph nodes (ALNs) of patients with biopsy-proven breast cancer., Methods: A review of our institution's surgical and pathologic database was performed for patients with pathologically proven axillary ENE from October 1, 2003, to October 1, 2007. An equivalent number of patients without ENE were included. All patients had sonograms of ALNs available. A radiologist to whom the study was masked reviewed ALN images with specific attention to unclear margins, node matting, perinodal edema, and hilar effacement or replacement. Univariate and multivariate logistic regression analyses were used to obtain the sensitivity, specificity, and odds ratio (OR) for each feature., Results: Our review included a total of 131 patients (64 with ENE and 67 without ENE). The respective sensitivity and specificity estimates for each feature were as follows: node matting, 52% and 84%; perinodal edema, 34% and 87%; unclear margins, 64% and 75%; hilar replacement, 71% and 42%; and hilar effacement, 74% and 60%. Univariate analysis showed a statistically significant association between features and ENE with ORs as follows: matting, 5.4; perinodal edema, 3.4; unclear margins, 5.2; and hilar replacement, 4.3. Multivariate analysis showed that matting and unclear margins were independently associated with ENE., Conclusions: The sonographic features of unclear margins, node matting, perinodal edema, and hilar replacement have a statistically significant association with ENE. The sonographic features of unclear margins, node matting, and perinodal edema predict ENE with high specificity.

Background: Lobular involution, or age-related atrophy of breast lobules, is inversely associated with breast cancer risk, and mammographic breast density (MBD) is positively associated with breast cancer risk., Methods: To evaluate whether lobular involution and MBD are independently associated with breast cancer risk in women with benign breast disease, we performed a nested cohort study among women (n = 2666) with benign breast disease diagnosed at Mayo Clinic between January 1, 1985, and December 31, 1991 and a mammogram available within 6 months of the diagnosis. Women were followed up for an average of 13.3 years to document any breast cancer incidence. Lobular involution was categorized as none, partial, or complete; parenchymal pattern was classified using the Wolfe classification as N1 (nondense), P1, P2 (ductal prominence occupying <25%, or >25% of the breast, respectively), or DY (extremely dense). Hazard ratios (HRs) and 95% confidence intervals (CIs) to assess associations of lobular involution and MBD with breast cancer risk were estimated using adjusted Cox proportional hazards model. All tests of statistical significance were two-sided., Results: After adjustment for MBD, having no or partial lobular involution was associated with a higher risk of breast cancer than having complete involution (none: HR of breast cancer incidence = 2.62, 95% CI = 1.39 to 4.94; partial: HR of breast cancer incidence = 1.61, 95% CI = 1.03 to 2.53; P(trend) = .002). Similarly, after adjustment for involution, having dense breasts was associated with higher risk of breast cancer than having nondense breasts (for DY: HR of breast cancer incidence = 1.67, 95% CI = 1.03 to 2.73; for P2: HR of breast cancer incidence = 1.96, 95% CI = 1.20 to 3.21; for P1: HR of breast cancer incidence = 1.23, 95% CI = 0.67 to 2.26; P(trend) = .02). Having a combination of no involution and dense breasts was associated with higher risk of breast cancer than having complete involution and nondense breasts (HR of breast cancer incidence = 4.08, 95% CI = 1.72 to 9.68; P = .006)., Conclusion: Lobular involution and MBD are independently associated with breast cancer incidence; combined, they are associated with an even greater risk for breast cancer.

Background: Completion axillary lymph node dissection (CALND) is controversial in patients with sentinel lymph node (SLN) metastases ≤ 0.2 mm [N0(i+)]. Our goal was to characterize patients with SLN isolated tumor cells regarding surgical management and axillary recurrence., Materials and Methods: An Institutional Review Board (IRB)-approved retrospective chart review identified 677 consecutive patients with positive SLN biopsy for breast cancer between October 1997 and June 2004, and N0(i+) patients were identified. Clinicopathologic characteristics, predicted probability of nonsentinel node disease, axillary surgery, and recurrences were recorded., Results: Of 81 patients with SLN N0(i+) metastasis, 31 underwent CALND and 50 did not. The two groups of patients showed no statistical differences in tumor size, stage, grade, number of SLNs removed, and number of positive SLNs. Predicted probability of additional axillary metastasis was somewhat higher among those who underwent CALND compared with those who did not. Patients undergoing CALND were significantly younger than those who did not (mean age 50 vs. 57, P = 0.01). Of the 31 patients with CALND, 4 (12.9%) had additional nodal metastases. Radiation to nodal fields was administered to 8 patients in the CALND group (25.8%) and to 7 in the group without axillary dissection (14.0%, P = 0.44). No axillary recurrences were noted at a median follow-up of 38 months., Conclusion: Among breast cancer patients with SLN isolated tumor cells, a small percentage have additional metastasis in other axillary nodes. However, the risk of axillary recurrence appears low in those who do not undergo CALND.

Background: Pure tubular carcinoma of the breast is a rare subtype with a low incidence of axillary lymph node metastases. The aim of this study was to determine the frequency of axillary lymph node metastasis in patients with pure tubular carcinoma., Methods: We identified patients diagnosed with tubular carcinoma from 1987 to 2009 from our institution's tumor registry. Pathology slides were reviewed, and pure tubular carcinoma was defined as ≥ 90% tubule formation, low nuclear grade, and rare to no mitoses. Medical records were reviewed for clinicopathologic data including tumor size, number of positive and negative axillary lymph nodes, treatment, and recurrence., Results: We identified 105 cases of pure tubular carcinoma of the breast in 103 patients. Median tumor size was 0.8 (range 0.1-1.8) cm. Nodal staging was performed in 93 cases (89%). Five patients (5.4%) had positive lymph nodes, and two patients (2.2%) had isolated tumor cells. All patients with lymph node metastases had tumors >0.8 cm in size. At 5.2 years' follow-up, no patients have developed recurrence or metastases, or have died from breast cancer., Conclusions: Axillary lymph node metastases are not common in small pure tubular carcinomas. Nodal staging may be omitted in small pure tubular carcinomas.

Uncontrolled proliferation is a defining feature of the malignant phenotype. Ki67 is a marker for proliferating cells and is overexpressed in many breast cancers. Atypical hyperplasia is a premalignant lesion of the breast (relative risk approximately 4.0). Here, we asked if Ki67 expression could stratify risk in women with atypia. Ki67 expression was assessed immunohistochemically by digital image analysis in archival sections from 192 women with atypia diagnosed at the Mayo Clinic 1/1/67-12/31/91. Risk factor and follow-up data were obtained via study questionnaire and medical records. Observed breast cancer events were compared to population expected rates (Iowa SEER) using standardized incidence ratios (SIRs). We examined two endpoints: risk of breast cancer within 10 years and after 10 years of atypia biopsy. Thirty-two (16.7%) of the 192 women developed breast cancer over a median of 14.6 years. Thirty percent (58) of the atypias had >or=2% cells staining for Ki67. In these women, the risk of breast cancer within 10 years after atypia was increased (SIR 4.42 [2.21-8.84]) but not in those with <2% staining. Specifically, the cumulative incidence for breast cancer at 10 years was 14% in the high Ki67 vs. 3% in the low Ki67 group. Conversely, after 10 years, risk in the low Ki67 group rose significantly (SIR 5.69 [3.63-8.92]) vs. no further increased risk in the high Ki67 group (SIR 0.78 [0.11-5.55]). Ki67 appears to be a time-varying biomarker of risk of breast cancer in women with atypical hyperplasia.

Objective: The purpose of our study was to describe the imaging findings in adenoid cystic carcinoma (ACC) of the breast, with pathologic and clinical correlation., Materials and Methods: We retrospectively searched our surgical database from January 1994 through December 2008 for cases of pathologically proven ACC of the breast. Of approximately 15,000 breast biopsies, 11,250 were malignant. Eleven cases of ACC (0.1% of all malignancies), all with imaging available for review, were included in the study., Results: Mammographically (n = 10), tumors appeared as developing asymmetric densities or irregular masses. Sonographically (n = 9), they appeared as irregular, heterogeneous, or hypoechoic masses with minimal vascularity on color Doppler imaging. MRI (n = 5)--because of better soft-tissue contrast and dedicated, multiplanar breast sequences--helped show the extent of the tumor, particularly if dense breast tissue obscured the mass on CT. Two cases with subtle sonographic findings were better delineated on MRI because of tumor enhancement. The solid variant showed increased signal intensity on T2-weighted imaging. ACC showed variable enhancement kinetics ranging from persistent enhancement to washout kinetics in the larger lesions. On molecular breast imaging (n = 1), the tumors showed avid uptake of radiotracer but did not always show activity on PET (n = 1). CT (n = 2) showed areas of rapid, nodular enhancement., Conclusion: Recognition of ACC is important to avoid delay in diagnosis because this tumor has a good prognosis with rare metastases to axillary lymph nodes. Axillary nodal sampling by fine-needle aspiration or core biopsy is rarely indicated.

Purpose: Mammographic density and lobular involution are both significant risk factors for breast cancer, but whether these reflect the same biology is unknown. We examined the involution and density association in a large benign breast disease (BBD) cohort., Patients and Methods: Women in the Mayo Clinic BBD cohort who had a mammogram within 6 months of BBD diagnosis were eligible. The proportion of normal lobules that were involuted was categorized by an expert pathologist as no (0%), partial (1% to 74%), or complete involution (>or= 75%). Mammographic density was estimated as the four-category parenchymal pattern. Statistical analyses adjusted for potential confounders and evaluated modification by parity and age. We corroborated findings in a sample of women with BBD from the Mayo Mammography Health Study (MMHS) with quantitative percent density (PD) and absolute dense and nondense area estimates., Results: Women in the Mayo BBD cohort (n = 2,667) with no (odds ratio, 1.7; 95% CI, 1.2 to 2.3) or partial (odds ratio, 1.3; 95% CI, 1.0 to 1.6) involution had greater odds of high density (DY pattern) than those with complete involution (P trend < .01). There was no evidence for effect modification by age or parity. Among 317 women with BBD in the MMHS study, there was an inverse association between involution and PD (mean PD, 22.4%, 21.6%, 17.2%, for no, partial, and complete, respectively; P trend = .04) and a strong positive association of involution with nondense area (P trend < .01). No association was seen between involution and dense area (P trend = .56)., Conclusion: We present evidence of an inverse association between involution and mammographic density.

Identification and prediction of breast cancer patients with metastases isolated to the sentinel lymph node(s) would potentially allow avoidance of axillary dissection and its complications. In this study, we evaluate the performance of two recently published models (Alkhatib et al. and Chagpar et al.) that attempt to predict patients who have isolated sentinel lymph node metastases. Both of these models reported a 5% rate of positive nonsentinel nodes in their respective lowest risk category. From 1997 to 2004, 465 breast cancer patients had a positive sentinel node and underwent axillary lymph node dissection at Mayo Clinic. To evaluate the Alkhatib model, patients were assigned to the following groups: group 1: 1 positive sentinel node and > or =1 negative sentinel node(s); group 2: >1 positive sentinel node and > or =1 negative sentinel node(s); group 3: 1 positive sentinel node and no negative sentinel node(s); group 4: >1 positive sentinel node and no negative sentinel node(s). To evaluate the Chagpar model, patients were assigned a score based on the sum of three factors: tumor size (T1a = 1, T1b or T1c = 2, T2 = 3, and T3 = 4 points), number of positive sentinel nodes (>1 positive sentinel node = 1 point), and ratio of positive/total sentinel nodes (>50% positive = 1 point). The chi-square test was used to compare our results to those of the original studies. For the Alkhatib model, we found that 30% (p < 0.0001) of Group 1 patients had nonsentinel node metastases. Using the Chagpar model, the percentage of patients with a cumulative score of 1 with a nonsentinel node metastasis was 17% (p = 0.19). In our cohort, neither model accurately predicted which patients have a < or = 5% chance of having nonsentinel metastases. These models are not adequate to identify patients in whom axillary dissection can be omitted.

We previously identified a SNF1/AMPK-related protein kinase, Hunk, from a mammary tumor arising in an MMTV-neu transgenic mouse. The function of this kinase is unknown. Using targeted deletion in mice, we now demonstrate that Hunk is required for the metastasis of c-myc-induced mammary tumors, but is dispensable for normal development. Reconstitution experiments revealed that Hunk is sufficient to restore the metastatic potential of Hunk-deficient tumor cells, as well as defects in migration and invasion, and does so in a manner that requires its kinase activity. Consistent with a role for this kinase in the progression of human cancers, the human homologue of Hunk is overexpressed in aggressive subsets of carcinomas of the ovary, colon, and breast. In addition, a murine gene expression signature that distinguishes Hunk-wild type from Hunk-deficient mammary tumors predicts clinical outcome in women with breast cancer in a manner consistent with the pro-metastatic function of Hunk in mice. These findings identify a direct role for Hunk kinase activity in metastasis and establish an in vivo function for this kinase.

Background: Several models for the prediction of nonsentinel lymph node (NSLN) metastasis in sentinel lymph node (SLN)-positive breast cancer patients have been proposed. In this study, the authors evaluate the Stanford Online Calculator (SOC), which was designed to predict the likelihood of NSLN metastasis using only 3 variables: primary tumor size, SLN metastasis size, and angiolymphatic invasion status. They compared it with the Mayo and Memorial Sloan-Kettering Cancer Center (MSKCC) nomograms., Methods: The SOC was used to calculate the probability of NSLN metastasis in 464 breast cancer patients with SLN metastasis who underwent completion axillary lymph node dissection at the Mayo Clinic. The area under the receiver operating characteristic curve (AUC) was calculated for each model. Mean probabilities of patients with and without NSLN metastasis were compared. Patients with

Background: We sought to determine how often axillary node metastases were present in patients with intramammary lymph node (IMLN) metastasis and if the method of IMLN discovery impacts likelihood of axillary node metastasis., Methods: A retrospective review of our breast cancer database was conducted to identify patients in whom an IMLN was found. IMLNs were classified into 2 groups: those found "preoperatively" (evident on mammography, ultrasonography, magnetic resonance imaging or lymphogram), and those found "incidentally" (found by the surgeon intraoperatively or on pathologic review). Patterns of discovery and their correlation with axillary disease were evaluated using Fisher's exact test., Results: Between March 1994 and October 2007, IMLNs were identified in 93 breast specimens. Twenty-three IMLNs were found preoperatively, while 70 were identified incidentally. Thirty-two patients (34%) harbored cancer in IMLNs with additional axillary node involvement present in 22 (69%). Metastasis was more frequent in the IMLNs detected by imaging (10/23, 43%) than in IMLNs detected incidentally (22/70, 31%, P = NS). Patients with positive IMLNs were more likely to have axillary disease than patients with negative IMLNs (69% versus 18%, P < .0001)., Conclusion: The majority of identified IMLNs are histologically negative. If breast cancer is identified in an IMLN, additional axillary lymph node disease is common, regardless of the method of detection of the IMLN.

Calcifying fibrous pseudotumor (CFP) is classified as a benign fibrous lesion, and is a rare pathologic entity. Previous reports have described CFPs in the extremities, chest wall, pleura, scrotum, mediastinum, neck, and visceral peritoneum. We present the first reported case of a CFP in the breast. CFP should be considered in the differential diagnosis for patients presenting with coarse indeterminate calcifications of the breast.

Purpose: An accurate estimate of a woman's breast cancer risk is essential for optimal patient counseling and management. Women with biopsy-confirmed atypical hyperplasia of the breast (atypia) are at high risk for breast cancer. The Gail model is widely used in these women, but has not been validated in them., Patients and Methods: Women with atypia were identified from the Mayo Benign Breast Disease (BBD) cohort (1967 to 1991). Their risk factors for breast cancer were obtained, and the Gail model was used to predict 5-year-and follow-up-specific risks for each woman. The predicted and observed numbers of breast cancers were compared, and the concordance between individual risk levels and outcomes was computed., Results: Of the 9,376 women in the BBD cohort, 331 women had atypia (3.5%). At a mean follow-up of 13.7 years, 58 of 331 (17.5%) patients had developed invasive breast cancer, 1.66 times more than the 34.9 predicted by the Gail model (95% CI, 1.29 to 2.15; P < .001). For individual women, the concordance between predicted and observed outcomes was low, with a concordance statistic of 0.50 (95% CI, 0.44 to 0.55)., Conclusion: The Gail model significantly underestimates the risk of breast cancer in women with atypia. Its ability to discriminate women with atypia into those who did and did not develop breast cancer is limited. Health care professionals should be cautious when using the Gail model to counsel individual patients with atypia.

Background: Limited studies have examined the associations between mammographic density and subsequent breast tumor characteristics., Methods: Eligible women were part of a case-control study of postmenopausal breast cancer, were 40 years or older and had a routine mammogram 4 years or more before their diagnosis. Mammographic density (percent density, dense area, and nondense area) was estimated using a computer-assisted thresholding program. At the time of cancer diagnosis, cases were classified as asymptomatic or symptomatic based on medical record review and breast imaging workup. Pathologic review was done blinded to the density status. Linear regression models and tests for trend examined the association between pathologic characteristics of the breast tumor and the components of density for all participants, and stratified by symptom status at diagnosis., Results: Of the 286 eligible cases, 77% were 60 years or older and mean percent density was 29.5% (SD, 14.6%). Density was not significantly associated with tumor size (P = 0.22), histologic type (P = 0.77), estrogen receptor (P = 0.11) or progesterone receptor (P = 0.37) status, mitotic activity (P = 0.12), or nuclear pleomorphism (P = 0.09; P values for percent density). An inverse association was suggested between tumor grade and percent density (32.0%, 30.3%, 26.7% for grades 1-3; P = 0.06 for trend). The inverse association with tumor grade and its components (nuclear pleomorphism and tubular differentiation) was only evident among the 97 symptomatic women; positive associations of estrogen receptor (P = 0.009) and progesterone receptor (P = 0.04) were also seen with percent density only in this subgroup., Conclusions: The inverse association between tumor grade and percent density in the symptomatic population could inform the biology of the association between mammographic density and breast cancer risk.

Background: The cyclooxygenase-2 (COX-2) enzyme, which is induced by inflammatory and mitogenic stimuli, plays a protumorigenic role in several human cancers. COX-2 is overexpressed in invasive and in situ breast cancers. Atypical hyperplasia in breast tissue, although benign, is associated with a high risk of breast cancer. We investigated whether COX-2 overexpression in atypical hyperplasia is associated with the risk of subsequent breast cancer., Methods: COX-2 expression was assessed immunohistochemically in archival sections from 235 women with atypia whose biopsy specimens were obtained at the Mayo Clinic from January 1, 1967, through December 31, 1991. COX-2 expression was scored as 0 (negative), 1+ (weak), 2+ (moderate), or 3+ (strong). Risk factor information and follow-up for breast cancer events were obtained via a study questionnaire and the medical records. All statistical tests were two-sided., Results: Forty-one (17%) of the 235 women developed breast cancer during a median follow-up of 15 years. Moderate (category 2+) or strong (category 3+) COX-2 expression was identified in 71 (30%) and 34 (14%) of the 235 samples, respectively. The risk for developing breast cancer, relative to a control population (the Iowa Surveillance, Epidemiology, and End Results registry), increased with increasing COX-2 expression (relative risk [RR] = 2.63, 95% confidence interval [CI] = 1.56 to 4.15, for those with negative or weak COX-2 expression; RR = 3.56, 95% CI = 1.94 to 5.97, for those with moderate expression; and RR = 5.66, 95% CI = 2.59 to 10.75, for those with strong expression; P = .07). Overexpression of COX-2 was statistically significantly associated with the type of atypia (lobular vs ductal, P < .001), number of foci of atypia in the biopsy (P = .02), and older age at time of biopsy (>45 years, P = .01)., Conclusions: COX-2 appears to be a biomarker that further stratifies breast cancer risk among women with atypia and may be a relevant target for chemoprevention strategies.

Objective: This article describes the imaging findings, pathologic correlation, and clinical presentation of rare primary and secondary angiosarcomas of the breast., Conclusion: With the increasing use of breast conservation therapy for breast cancer, reports of postirradiation angiosarcoma have increased. Both primary and secondary angiosarcomas may present with bruiselike skin discoloration, which may delay the diagnosis. Imaging findings are nonspecific. MRI may be used to determine lesion extent by showing rapid enhancement and washout in high-grade tumors.

Objective: This report describes the sonographic features of 2 patients with invasive carcinoma of the breast that sonographically mimicked benign epithelial cysts of the areola., Methods: We retrospectively reviewed 2 cases of invasive ductal carcinoma that initially were diagnosed as dermal lesions in the areola after sonographic evaluation., Results: Sonographically, the 2 lesions were centered between the echogenic lines of the deep dermis of the areola. Neither sonogram showed a deeper component arising from the underlying breast tissue that would suggest a breast origin., Conclusions: Lesions in the subcutaneous tissue superficial to the anterior pectoral fascia are extraparenchymal in origin and typically are benign. The areolar tissue, however, is not extraparenchymal because the dermis of the areola contains lactiferous ducts; these ducts extend from a more deeply placed mammary gland and are associated with modified sebaceous glands. All types of breast abnormalities, including malignancies, may affect deeper lactiferous glands and ducts and extend into the areola, independent of nipple involvement.

Background: Tamoxifen is biotransformed to the potent anti-estrogen, endoxifen, by the cytochrome P450 (CYP) 2D6 enzyme. CYP2D6 genetic variation and inhibitors of the enzyme markedly reduce endoxifen plasma concentrations in tamoxifen-treated patients. Using a North Central Cancer Treatment Group adjuvant tamoxifen trial, we performed a comprehensive evaluation of CYP2D6 metabolism by assessing the combined effect of genetic variation and inhibition of the enzyme system on breast cancer recurrence and death., Methods: Medical records were reviewed at each randomizing site to determine whether CYP2D6 inhibitors were co-prescribed with tamoxifen. Extensive metabolizers were defined as patients without a *4 allele (i.e., wt/wt) who were not co-prescribed a CYP2D6 inhibitor. Patients with decreased CYP2D6 metabolism were classified as intermediate or poor metabolizers (PM) based on the presence of one or two CYP2D6*4 alleles or the co-administration of a moderate or potent CYP2D6 inhibitor. The association between CYP2D6 metabolism and clinical outcome was assessed using Cox modeling., Results: Medication history was available in 225/256 eligible patients and CYP2D6*4 genotype in 190 patients. Thirteen patients (6%) were co-prescribed a CYP2D6 inhibitor [potent (n = 3), moderate (n = 10)], resulting in the following CYP2D6 metabolism: extensive (n = 115) and decreased (n = 65). In the multivariate analysis, patients with decreased metabolism had significantly shorter time to recurrence (p = 0.034; adj HR = 1.91; 95% CI 1.05-3.45) and worse relapse-free survival (RFS) (p = 0.017; adj HR = 1.74; 1.10-2.74); relative to patients with extensive metabolism. Cox' modeling demonstrated that compared to extensive metabolizers, PM had the most significant risk of breast cancer relapse (HR 3.12, p = 0.007)., Conclusion: CYP2D6 metabolism, as measured by genetic variation and enzyme inhibition, is an independent predictor of breast cancer outcome in post-menopausal women receiving tamoxifen for early breast cancer. Determination of CYP2D6 genotype may be of value in selecting adjuvant hormonal therapy and it appears CYP2D6 inhibitors should be avoided in tamoxifen-treated women.

Purpose: Polymorphisms in tamoxifen metabolizing genes affect the plasma concentration of tamoxifen metabolites, but their effect on clinical outcome is unknown., Methods: We determined cytochrome P450 (CYP)2D6 (*4 and *6) and CYP3A5 (*3) genotype from paraffin-embedded tumor samples and buccal cells (living patients) in tamoxifen-treated women enrolled onto a North Central Cancer Treatment Group adjuvant breast cancer trial. The relationship between genotype and disease outcome was determined using the log-rank test and Cox proportional hazards modeling., Results: Paraffin blocks were obtained from 223 of 256 eligible patients, and buccal cells were obtained from 17 living women. CYP2D6 (*4 and *6) and CYP3A5 (*3) genotypes were determined from 190, 194, and 205 patient samples and in 17 living women. The concordance rate between buccal and tumor genotype was 100%. Women with the CYP2D6 *4/*4 genotype had worse relapse-free time (RF-time; P = .023) and disease-free survival (DFS; P = .012), but not overall survival (P = .169) and did not experience moderate to severe hot flashes relative to women heterozygous or homozygous for the wild-type allele. In the multivariate analysis, women with the CYP2D6 *4/*4 genotype still tended to have worse RFS (hazard ratio [HR], 1.85; P = .176) and DFS (HR, 1.86; P = .089). The CYP3A5*3 variant was not associated with any of these clinical outcomes., Conclusion: In tamoxifen-treated patients, women with the CYP2D6 *4/*4 genotype tend to have a higher risk of disease relapse and a lower incidence of hot flashes, which is consistent with our previous observation that CYP2D6 is responsible for the metabolic activation of tamoxifen to endoxifen.

Background: Breast cancer metastatic to the gastrointestinal tract or peritoneum is rare. We reviewed the natural history of ductal and lobular carcinoma in women with breast cancer metastatic to the gastrointestinal tract, peritoneum, or both., Methods: We performed a retrospective review of all patients (1985-2000) with a pathologic diagnosis of breast cancer metastatic to the gastrointestinal tract or peritoneum. Patients were categorized into three groups: those with gastrointestinal metastasis, carcinomatosis, or both., Results: Of 73 patients, 23 (32%) had gastrointestinal metastasis only, 32 (44%) had carcinomatosis only, and 18 (25%) had both. The median age at initial breast cancer diagnosis was 55 years. The mean interval between the primary diagnosis and metastatic presentation was 7 years. Sites of gastrointestinal metastases included the esophagus (8%), stomach (28%), small intestine (19%), and colon and rectum (45%). Infiltrating lobular carcinoma represented 34 (64%) of the 53 gastrointestinal metastases. The median overall survival after diagnosis was 28 months. Palliative surgical intervention in 47 patients (64%) did not affect overall survival. Some survival benefit may have accrued to select patients with gastrointestinal metastasis who underwent surgical palliation (44 vs. 9 months). Advanced age at diagnosis and gastric metastases had a negative effect on survival, whereas treatment with systemic chemotherapy or tamoxifen had a positive effect on survival., Conclusions: Gastrointestinal metastasis occurred more often in patients with invasive lobular carcinoma. Surgical intervention did not significantly extend overall survival but may be considered in a select group of patients.

Background: The accurate prediction of nonsentinel node (NSN) metastasis in breast cancer patients remains uncertain., Methods: The medical records of 574 breast cancer patients from 2 different institutions (Mayo Clinic and University of Michigan) with sentinel lymph node biopsy examination and completion axillary lymph node dissection were reviewed for multiple clinicopathologic variables. The Memorial Sloan Kettering Cancer Center nomogram performance for prediction of NSN metastases was assessed. A new model was developed with clinically relevant variables and possible advantages., Results: The Memorial Sloan Kettering Cancer Center nomogram predicted the likelihood of NSN metastasis with an area under the receiver operating characteristic curve of .72 and .86. For predicted probability cut-off points of 5% and 10%, the false-negative rates were 0% and 14% (Mayo), and 17% and 11% (Michigan). A new model was developed with similar area under the curve but lower false-negative rates for low-probability subgroups., Conclusions: Predictive models for NSN tumor burden are imperfect.

Fluorescence in situ hybridization (FISH) and immunohistochemical analysis for assessment of HER-2 status in breast carcinomas are discordant in a significant proportion of cases with equivocal (2+) immunostaining. To evaluate the role of intratumoral heterogeneity and degree of amplification, we performed additional HER-2 immunostains and FISH on tumor-bearing blocks from 20 invasive breast carcinomas with immunohistochemical scores of 2+ with gene amplification and in 18 cases without amplification. Of the amplified cases, 11 (55%) had a 3+ immunohistochemical score on at least 1 additional slide, 8 (40%) remained 2+, and 1 (5%) had a slide scored 1+. All cases rescored 3+ showed high-level amplification in original and repeated FISH; cases remaining 2+ had a heterogeneous FISH profile (low-level amplification or a mosaic mixture of high-level amplified and nonamplified cells) in original and repeated FISH. Of nonamplified cases, 13 (72%) had a 1+ score on at least 1 additional slide, 4 (22%) remained 2+, and 1 (6%) had 1 slide scored 3+. In the nonamplified cases, 17 (94%) showed no amplification in repeated FISH. Significant intratumoral heterogeneity and minimal (low-level) HER-2 amplification account for many breast cancers with 2+ HER-2 protein expression.

Background: Malignant phyllodes tumor (MPT) is a rare but aggressive breast malignancy. The aim of this study was to evaluate parameters that influence outcome in patients with MPT., Methods: Fifty women were diagnosed with MPT of the breast and treated between August 1971 and July 2000. All medical records were reviewed retrospectively. The Cox regression model was used for multivariate analysis., Results: Tumors were classified as borderline (6%), low grade (32%), or high grade (62%). The median patient age was 46 years (range, 14-77 years). The median tumor diameter was 3.5 cm (range, 1.5-18 cm). Twenty-two patients had wide local excision (WLE), and 28 patients had mastectomy. The median follow-up was 91 months (range, 12-360 months). Local recurrence (LR) occurred in 16 patients (32%) an average of 26 months after surgery (median, 17 months; range, 3-72 months). Distant metastasis occurred in 13 patients (26%) at an average of 53.4 months (median, 36 months; range, 4-177 months). Sixteen (32%) patients have died of their disease. LR was significantly increased with stromal overgrowth (P < .0001), large tumor size (P = .0177), and surgical margins <1 cm (P = .0120), but not with WLE (P = .5099). Stromal overgrowth was the only independent variable predictive of systemic metastasis (P < .0001) and patient survival (P < .0001)., Conclusions: Stromal overgrowth in MPT carries a grave prognosis. Close surgical margins and large tumor size, but not type of operation, significantly increased LR. Either WLE with adequate margins or mastectomy is an appropriate treatment for patients with MPT.

Primary sarcomas of the breast are extremely rare, with less than 0.1% of all malignant tumours of the breast. Mayo Clinic Surgical Pathology database was searched for all breast sarcoma from 1910 to 2000. Pathology reports and slides were reviewed and tumour types were determined. Metaplastic carcinomas and phyllodes tumours were excluded. There were 25 women ranging in age 24-81 years (mean 45 years). All but one patient presented with a palpable lump. Mastectomy was performed in 19 patients and lumpectomy in five patients. Histopathological diagnoses were fibrosarcoma (six), angiosarcoma (six), pleomorphic sarcoma (six), leiomyosarcoma (two), myxofibrosarcoma (three), hemangiopericytoma (one) and osteosarcoma (one). Tumour size ranged from 0.3 to 12 cm (mean 5.7). Low-grade lesions were observed in 10 cases and high-grade in 15. Overall, mean follow-up was 10.5 years. Local recurrence was observed in 11 patients and ranged from 2 to 36 months (mean 15 m), while distant metastasis was observed in 10 patients (40%) affecting lungs, bones, liver, spleen, and skin. Of the 25 patients, 12 have died of disease and six of other causes. Five-year overall (OS) and cause-specific survival (CSS) were 66 and 70%, respectively. OS and DFS at 5 years were 91% for tumours < or =5 cm and 50% for tumours >5 cm. Tumour size was significantly associated with OS (risk ratio=1.3 per 1 cm increase; 95% CI, 1.02-1.7; P=0.036). There was no significant difference in OS or CSS between low- and high-grade lesions. In this series, tumour size was a more valuable prognostic factor than tumour grade.

Sporadic cancers and familial breast cancers are characterized by an increase in genetic instability. Little is known about whether mismatch repair defects accompany this genetic instability. We investigated invasive and/or in situ breast cancers from 30 women with deleterious BRCA1/2 mutations and unclassified variant BRCA1/2 alterations. Forty cases of sporadic breast cancers were also investigated, including 7 medullary carcinomas. Malignant and benign lesions were examined from all cases to better understand tumor progression. Automated immunohistochemistry, with antibodies directed against hMLH1 and hMSH2, was used to screen cases for possible mismatch repair defects. When loss of expression was noted, DNA ploidy was performed by cytomorphometry. DNA, after laser microdissection, was extracted from a majority of familial cases and their corresponding controls, and microsatellite instability analysis was performed. None of the familial or sporadic cases had loss of hMSH2 expression. All but one lesion, a DCIS arising in a deleterious BRCA2 mutation carrier, had loss of hMLH1 expression and a tetraploid profile by image cytomorphometry. There was no MSI in any explored lesions (n = 34), as determined by molecular analysis, including the DCIS with loss of hMLH1 expression. We conclude that DNA mismatch repair defects involving hMLH1 and hMSH2 underexpression are extremely rare events in sporadic and familial breast cancer. Mismatch repair gene mutations may be secondary random events in breast cancer progression., (Copyright 2003 Wiley-Liss, Inc.)

Microglandular adenosis (MGA) is a well-recognized, if rare and incompletely characterized, entity in which carcinoma is rarely thought to develop. We report 17 cases in which patterns of adenoid cystic carcinoma (ACC) coexisted with MGA. Immunocharacterization with beta-catenin, E-cadherin, cytokeratins (AE1/AE3), epithelial membrane antigen, S-100 protein, smooth muscle actin, and vimentin was also performed. Most cases had areas of invasive ACC characterized by its defining dual-lumen types. Some cases of ACC appeared to have expanded glands intermingled within the MGA, whereas in other cases ACC formed a transition with the characteristic small, gland-like spaces of MGA. MGA and "atypical MGA" stained irregularly and similarly to that seen in myoepithelium with the three markers of myoepithelial cells in breast: S-100 protein, smooth muscle actin, and vimentin. These markers were also positive in the more solid elements of the ACC. Our study suggests that ACC may develop in a background of and in continuity with MGA. Altered myoepithelial cells appear to be the major neoplastic element in both ACC and "atypical MGA." "Atypical MGA" with transition to ACC may show histologic patterns and an immunohistochemical profile similar to that of ACC. These lesions might be best interpreted as ACC in situ. Both MGA and ACC of the breast grow in an expansile and diffusely infiltrative pattern without having significant metastatic capacity. Their unusual interaction with the surrounding stroma may play a role in this benign biologic behavior.

Background: Breast magnetic resonance imaging (MRI) is a developing technique for the evaluation of patients with primary breast carcinoma. The authors assessed the impact of preoperative breast MRI on surgical management., Methods: The current study was a retrospective review of 267 patients with primary breast tumors who had MRI studies prior to undergoing definitive surgery., Results: Two hundred sixty-seven patients with invasive breast carcinoma who had preoperative breast MRI studies and had complete clinical, radiologic, and pathologic data available were identified and formed the basis of this analysis. The overall sensitivity of MRI for detecting primary, intact breast tumors was 95%. Planned surgical management was altered in 69 of 267 patients (26%); and, in 49 of those patients (71%), there was pathologic verification of malignancy in the surgical specimen that confirmed the need for wider or separate excision or mastectomy. Forty-four of 267 patients (16.5%) had conversion of planned breast conservation to mastectomy. In a univariate analysis, change in management was associated significantly with histology; management was altered in 11 of 24 lobular tumors (46%) compared with 58 of 243 ductal tumors (24%; P = 0.02)., Conclusions: Breast MRI was very sensitive for the detection of primary, intact, invasive breast carcinoma and improved local staging in almost 20% of patients. Preoperative breast MRI studies may be particularly useful in surgical planning for and management of patients with lobular carcinoma., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11490)

Hypothesis: Axillary relapse in node-negative patients staged with sentinel lymph node (SLN) biopsy alone is no more frequent than in patients treated with standard axillary dissection. Morbidity is less for patients who had SLN biopsy., Design, Setting, and Patients: Between October 14, 1997, and August 31, 2001, 1253 consecutive women with primary invasive breast cancer were prospectively entered into an SLN biopsy database. Completion axillary dissection was performed in 164 patients after SLN biopsy as part of a training protocol., Interventions: Patients were contacted by questionnaire or telephone to determine breast cancer relapse; presence of arm lymphedema, arm pain, axillary infection, or seroma formation; and tumor recurrence or death., Main Outcome Measures: chi2 or Fisher exact tests and Wilcoxon rank sum tests were used to analyze categorical and continuous variables. Logistic regression was used to analyze morbidity., Results: Of 1253 women, 894 (71%) were node negative by SLN biopsy alone (n = 730 [82%]) or SLN biopsy and completion axillary dissection (n = 164 [18%]). Questionnaires were completed by 776 patients (87%). Mean +/- SD follow-up was 2.4 +/- 0.9 years. Patients with axillary dissections reported a significantly higher occurrence of arm lymphedema (34%), arm pain (38%), seroma formation (24%), and infection (9%) vs SLN biopsy-only patients (6%, 14%, 7%, and 3%, respectively). One axillary relapse (0.1%) occurred during follow-up of 685 women who underwent SLN biopsy only., Conclusions: With intermediate-term follow-up, there was 1 axillary recurrence in 685 SLN node-negative women, supporting use of SLN biopsy as an accurate method for staging breast cancer. Biopsy of the SLN was associated with significantly less morbidity than completion axillary dissection.