Fit-for-Purpose Ki-67 Immunohistochemistry Assays for Breast Cancer.

New therapies are being developed for breast cancer and in this process some "old" biomarkers are re-utilized and given a new purpose. It is not always recognized that, by changing a biomarker's intended use, a new biomarker assay is created. The Ki-67 biomarker is typically assessed by immunohistochemistry (IHC) to provide a proliferative index in breast cancer. Canadian laboratories assessed the analytical performance and diagnostic accuracy of their Ki-67 IHC laboratory developed tests (LDTs), of relevance for the LDTs' clinical utility. Canadian clinical IHC laboratories enrolled in the Canadian Biomarker Quality Assurance (CBQA) Pilot Run for Ki-67 in breast cancer by invitation. The Dako Ki-67 IHC pharmDx assay was employed as a study reference assay. The Dako central laboratory (USA) was the reference laboratory. Participants received unstained slides of breast cancer tissue microarrays (TMAs) with 32 cases and performed their in-house Ki-67 assay. The results were assessed using QuPath, an open-source software for bio-image analysis. Positive percent agreement (PPA, sensitivity) and negative percent agreement (NPA, specificity) were calculated against the Dako Ki-67 IHC pharmDx assay for 5%, 10%, 20% and 30% cut-offs. Overall, PPA and NPA varied depending on the selected cut-off; participants were more successful with 5% and 10%, than with 20% and 30% cut-offs. Only four out of 16 laboratories had robust IHC protocols with acceptable PPA for all cut-offs. The lowest PPA for the 5% cut-off was 85%, for 10% was 63%, for 20% was 14%, and for 30% was 13%. The lowest NPA for the 5% cut-off was 50%, for 10% was 33%, for 20% was 50%, and for 30% was 57%. Despite many years of international efforts to standardize IHC testing for Ki-67 in breast cancer, our results indicate that Canadian clinical LDTs have a wide analytical sensitivity range and poor agreement for 20% and 30% cut-offs. The poor agreement was not due to the readout, but rather due to IHC protocol conditions. IKWG recommendations related to Ki-67 IHC standardization cannot take full effect without reliable fit-for-purpose reference materials that are required for the initial assay calibration, assay performance monitoring, and proficiency testing.

Metastatic Mammary Carcinoma Presenting as a Large Cystic Axillary Mass: A Report of an Unusual Case.

The differential diagnosis of cystic axillary masses is broad and includes intranodal lesions. Cystic metastatic tumor deposits are rare, and have been reported in a few tumor types, most commonly in the head and neck region, but rarely described with metastatic mammary carcinoma. We report a case of a 61-year-old female who presented with a large right axillary mass. Imaging studies revealed a cystic axillary mass and ipsilateral breast mass. She was managed with breast conservation surgery and axillary dissection for invasive ductal carcinoma, no special type, Nottingham grade 2 (21 mm). One of nine lymph nodes contained a cystic nodal deposit (52 mm), which resembled a benign inclusion cyst. Oncotype DX recurrence score for the primary tumor was low (8), conferring a low risk of disease recurrence despite the large size of the nodal metastatic deposit. A cystic pattern of metastatic mammary carcinoma is rare and important to recognize for accurate staging and management decisions.

Using Deep Learning to Predict Final HER2 Status in Invasive Breast Cancers That are Equivocal (2+) by Immunohistochemistry.

Invasive breast carcinomas are routinely tested for HER2 using immunohistochemistry (IHC), with reflex in situ hybridization (ISH) for those scored as equivocal (2+). ISH testing is expensive, time-consuming, and not universally available. In this study, we trained a deep learning algorithm to directly predict HER2 gene amplification status from HER2 2+ IHC slides. Data included 115 consecutive cases of invasive breast carcinoma scored as 2+ by IHC that had follow-up HER2 ISH testing. An external validation data set was created from 36 HER2 IHC slides prepared at an outside institution. All internal IHC slides were digitized and divided into training (80%), and test (20%) sets with 5-fold cross-validation. Small patches (256×256 pixels) were randomly extracted and used to train convolutional neural networks with EfficientNet B0 architecture using a transfer learning approach. Predictions for slides in the test set were made on individual patches, and these predictions were aggregated to generate an overall prediction for each slide. This resulted in a receiver operating characteristic area under the curve of 0.83 with an overall accuracy of 79% (sensitivity=0.70, specificity=0.82). Analysis of external validation slides resulted in a receiver operating characteristic area under the curve of 0.79 with an overall accuracy of 81% (sensitivity=0.50, specificity=0.82). Although the sensitivity and specificity are not high enough to negate the need for reflexive ISH testing entirely, this approach may be useful for triaging cases more likely to be HER2 positive and initiating treatment planning in centers where HER2 ISH testing is not readily available.

HER2 testing in metastatic breast cancer - Is reflex ISH testing necessary on HER2 IHC-equivocal (2+) cases?

Current guidelines recommend HER2 testing on all primary invasive breast cancers and re-biopsy at disease relapse. The discordance rate between HER2-negative primaries and HER2 IHC2+ metastases that are ISH-amplified is unknown. We hypothesize that the majority of such cases are non-amplified. ISH testing is time-consuming and resource-intensive, and there may be situations where it is unnecessary. A retrospective review of IHC2+ metastatic lesions assessed with ISH at our center from 2013 to 2021 was undertaken. 105 cases were identified after exclusion of cases missing HER2 results, with primaries of unconfirmed origin, and cases of synchronous primary and metastatic disease. IHC and ISH results were recorded with detailed slide review of discordant cases. 91/105 metastases had HER2-negative primaries (87%). A metastasis was significantly more likely to be HER2-negative when the primary was HER2-negative (93%) versus positive (43%) (p < 0.0001). 54/91 primaries were IHC2+/ISH-non-amplified, and 50/54 (93%) corresponding metastases had identical results. Of the 37 HER2-negative primaries that were IHC0/1+, 35 (95%) corresponding metastases were ISH-non-amplified. Six metastases in cases with HER2-negative primaries were discordant. Characteristics of metastases suggesting ISH testing was warranted to assess for discordance included IHC heterogeneity, morphological discordance, increased staining of moderate intensity, and ER/PR discordance. One or more of these factors were present in all discordant metastases. Our results suggest selective ISH testing on HER2 IHC2+ breast cancer metastases in the context of HER2-negative primary disease may be appropriate when there is careful review of the IHC. Validation of our findings awaits further studies with larger sample sizes.

Assessment of HER2 using the 2018 ASCO/CAP guideline update for invasive breast cancer: a critical look at cases classified as HER2 2+ by immunohistochemistry.

In 2018, the American Society of Clinical Oncology/College of American Pathologists revised the criteria for HER2 immunohistochemistry (IHC) equivocal (2+) classification in their updated guideline. We reviewed invasive breast cancer specimens originally classified as equivocal (2+) under the 2018 guideline that underwent HER2 fluorescence in situ hybridization (FISH) testing from August 2018 to August 2019 at our Canadian reference hospital to investigate cases with ambiguous staining patterns between the 1+ and 2+ definitions. Demographics, pathologic features, and pre-analytic conditions were recorded. The H&E and corresponding HER2 IHC slides were reviewed to confirm tumor type and grade, and classify as HER2 indeterminate, 0, 1+, 2+, or "Intermediate" (staining features between the 1+ and 2+ classifications). FISH testing was performed on 289 cases and 273 met inclusion criteria. The FISH-amplified rate was 12.1%. Upon IHC review, 44.7% (122/273) of cases were reclassified as Intermediate. These cases had incomplete staining with moderate intensity (43/122, 35.3%) and/or <10% complete weak or moderate staining (102/122, 83.6%). Intermediate cases had a significantly lower frequency of amplified FISH results than 2+ cases (p < 0.0001), with only four (3.3%) FISH positive and two (1.6%) FISH heterogeneous. Our study highlights the ambiguity in the current guideline for classifying some HER2 IHC patterns. As the rate of gene amplification in these cases was low (4.9%), we recommend adhering to the 2018 HER2 2+ criteria for reflex FISH testing. However, cases with <10% moderate complete staining and certain heterogeneous patterns warrant special consideration. Further descriptive clarification of 1+ criteria is needed.

Cystic neutrophilic granulomatous mastitis - a review of 12 consecutive cases.

AIMS: Cystic neutrophilic granulomatous mastitis (CNGM) is an uncommon but increasingly recognised cause of mastitis, often associated with Corynebacterium ssp. infection. We studied the histopathological and clinical features of CNGM in a Canadian setting, and the work-up required to identify pathogenic microorganisms. METHODS AND RESULTS: A retrospective search for breast specimens with abscess, acute, chronic and/or granulomatous inflammation from 1998 to 2018 was performed. Haematoxylin and eosin slides were reviewed for typical histological features of CNGM. Histochemically stained slides for microorganisms were also reviewed. Repeat Gram stains were performed if initially negative. Electronic medical records were abstracted for microbiology results and relevant clinical data. Twelve cases were identified. All were female, aged 25-57 years, mainly Caucasian, with one Venezuelan and two of Chinese ethnicity. Most were parous (10 of 12); five of 12 had an endocrinopathy. Bacteria were identified in one or more specimens from eight of 12 patients; additional Gram stains revealed organisms in four of 12 cases. Of four bacterial cultures, one grew Corynebacterium kroppenstedtii. 16S polymerase chain reaction for three samples was negative. Two patients had multiple breast biopsies, showing early palisaded granulomas followed by classic features of CNGM. The patients had various management approaches, including surgery and antimicrobials. CONCLUSIONS: CNGM may present as palisaded granulomatous inflammation, without the expected 'cystic' pattern, suggesting that there is an evolution of histomorphology with this infection. Most patients with CNGM are parous, and there may be an association with endocrinopathies. Application of multiple Gram stains increases the yield of microorganism identification. Recognition of CNGM in breast biopsies and collaborative communications are essential to direct appropriate therapy.

Assessing breast cancer risk within the general screening population: developing a breast cancer risk model to identify higher risk women at mammographic screening.

OBJECTIVES: To develop a breast cancer risk model to identify women at mammographic screening who are at higher risk of breast cancer within the general screening population. METHODS: This retrospective nested case-control study used data from a population-based breast screening program (2009-2015). All women aged 40-75 diagnosed with screen-detected or interval breast cancer (n = 1882) were frequency-matched 3:1 on age and screen-year with women without screen-detected breast cancer (n = 5888). Image-derived risk factors from the screening mammogram (percent mammographic density [PMD], breast volume, age) were combined with core biopsy history, first-degree family history, and other clinical risk factors in risk models. Model performance was assessed using the area under the receiver operating characteristic curve (AUC). Classifiers assigning women to low- versus high-risk deciles were derived from risk models. Agreement between classifiers was assessed using a weighted kappa. RESULTS: The AUC was 0.597 for a risk model including only image-derived risk factors. The successive addition of core biopsy and family history significantly improved performance (AUC = 0.660, p < 0.001 and AUC = 0.664, p = 0.04, respectively). Adding the three remaining risk factors did not further improve performance (AUC = 0.665, p = 0.45). There was almost perfect agreement (kappa = 0.97) between risk assessments based on a classifier derived from image-derived risk factors, core biopsy, and family history compared with those derived from a model including all available risk factors. CONCLUSIONS: Women in the general screening population can be risk-stratified at time of screen using a simple model based on age, PMD, breast volume, and biopsy and family history. KEY POINTS: • A breast cancer risk model based on three image-derived risk factors as well as core biopsy and first-degree family history can provide current risk estimates at time of screen. • Risk estimates generated from a combination of image-derived risk factors, core biopsy history, and first-degree family history may be more valid than risk estimates that rely on extensive self-reported risk factors. • A simple breast cancer risk model can avoid extensive clinical risk factor data collection.

Predictors of Outcome in Mammary Adenoid Cystic Carcinoma: A Multi-Institutional Study.

Mammary adenoid cystic carcinoma (ACC) is a rare subtype of breast cancer with a favorable prognosis. Here we report on predictors of outcome based on a detailed morphologic review and analysis of 108 mammary ACC. Sixty-four tumors (59.2%) were pure conventional ACC, 23 (21.3%) were pure basaloid ACC. Follow-up was available for 87 patients (median: 51 mo). Eighteen patients (20.7%) developed recurrence: 7 (8%) had local recurrence and 14 (16%) had distant metastasis. Two patients died of disease, 1 died of an unrelated cause, 14 were alive with disease (including 8 in palliative care), and 70 (80.5%) were alive with no evidence of disease. Of 90 patients with known lymph node (LN) status 9 (10%) had nodal involvement (all with basaloid ACC). Distant metastases in patients with predominantly basaloid ACC compared with pure conventional ACC were more common (40% vs. 7.7%) and occurred earlier (22 vs. 84 mo). The following factors were found to be predictive of recurrence-free survival: positive margin, Nottingham grade, neovascularization, basaloid component, perineural invasion, lymphovascular invasion, >30% solid growth, necrosis and LN involvement; the first 3 remained statistically significant on multivariate analysis. Factors predictive of distant disease-free survival were neovascularization, Nottingham grade, lymphovascular invasion, solid component >50%, LN involvement, basaloid component >50%, tumor necrosis, perineural invasion, and final margin. Only neovascularization remained statistically significant on multivariate analysis. Basaloid ACC is an aggressive variant of mammary ACC with more frequent nodal involvement and higher incidence of distant spread. LN staging should be performed for all mammary basaloid ACC.

Isolated Tumor Cells in Sentinel Lymph Nodes of Primary Invasive Breast Carcinoma: A Cohort Analysis.

BACKGROUND: The practice of performing routine cytokeratin immunohistochemistry (CK-IHC) on sentinel lymph nodes in early stage invasive breast cancer leads to frequent identification of isolated tumor cells (ITCs), the clinical significance of which remains unclear. After emergence of guidelines that suggested limited clinical utility of ITC detection, routine CK-IHC (rCK-IHC) staining was discontinued at our institution. We studied the rate and clinical utility of ITC detection before and after the discontinuation of rCK-IHC. PATIENTS AND METHODS: We retrospectively reviewed 2 cohorts of 250 consecutive early stage invasive breast cancer (IBC) patients with sentinel lymph node biopsies (SLNBs) in 2010 to 2011 (rCK-IHC) and 2015 to 2016 (selective CK-IHC [sCK-IHC]). Variables abstracted included: tumor histology, tumor size, grade, lymphatic-vascular invasion, hormone receptor expression, HER2 status, and nodal status including ITCs. All cases from the 2015 to 2016 cohort for which sCK-IHC was performed underwent pathology review. A clinical review of treatment decision effect and cost analysis was undertaken. Data were analyzed using descriptive statistics and Fisher exact test. RESULTS: In the rCK-IHC cohort, all 250 cases underwent CK-IHC staining versus 57 cases in the sCK-IHC cohort. There were 23 ITC cases observed in the rCK-IHC cohort compared with 11 in the sCK-IHC cohort (P = .049). Excluding lobular carcinomas, 19 ITC cases were observed with rCK-IHC versus 7 with sCK-IHC (P = .02). ITC detection did not affect adjuvant treatment decision-making and resulted in savings of at least Can$8000. CONCLUSION: Selective rather than routine use of CK-IHC staining for SLNB evaluation in early-stage IBC results in decreased ITC detection without affecting treatment decisions and leads to cost savings.

Impact of Detection Method and Age on Survival Outcomes in Triple-Negative Breast Cancer: A Population-Based Cohort Analysis.

BACKGROUND: Most investigations have compared triple-negative breast cancer (TNBC) to non-TNBC to elucidate clinical or epidemiologic differences between subtypes. We examined a contemporary cohort of patients with primary TNBC by detection and age at diagnosis within a population-based breast screening program to examine survival outcomes. PATIENTS AND METHODS: All women with a diagnosis of primary TNBC between January 1, 2005, and December 31, 2012, in Nova Scotia, Canada, were included. Clinicopathologic and detection variables were abstracted from the Nova Scotia Breast Screening Program. Patient charts were abstracted for adjuvant therapies and survival outcomes, supplemented by provincial vital statistical data. RESULTS: A total of 412 patients comprised the study population, with almost half aged over 60 years (46.3%) and 30.2% having screen-detected disease. There were no significant differences in prognostic variables between age groups. Younger patients were more likely to receive adjuvant chemotherapy (96.3% ≤ 49 years vs. 31.2% ≥ 70 years), but there were no differences in disease-free or breast cancer-specific survival between the age groups. For those with disease recurrence, median time to recurrence and death was shorter for younger patients (17 vs. 26 months, 16 vs. 33 months respectively; age 40-49 vs. 70+). Those with screen-detected disease had better disease-free, breast cancer-specific, and overall survival outcomes. CONCLUSION: Detection method may play a role in TNBC survival outcomes, thus supporting novel screening strategies for TNBC. Shorter time to survival events in the younger patient groups suggests that TNBC is a clinically heterogeneous disease despite similarities in prognostic factors across age.

Postirradiation pseudosclerodermatous panniculitis with involvement of breast parenchyma: a dramatic example of a rare entity and a pitfall in diagnosis.

Postirradiation pseudosclerodermatous panniculitis is a rare complication of external beam radiotherapy. This inflammatory process typically presents as an erythematous indurated plaque in a previously irradiated region of skin. To date, 13 cases have been reported worldwide. We present a case of a 70-year-old female who received breast irradiation following conservation surgery for invasive breast carcinoma. In her third year of follow-up, she developed an enlarging mass, involving the subcutis and underlying breast tissue, associated with mammographically detected coarse calcifications and density, at the surgical site. This was deemed highly suspicious of recurrent malignancy. Following several benign needle core biopsies, she had an excision of the mass. This revealed a lobular panniculitis and irradiation-induced vascular changes affecting subcutaneous fat and underlying breast tissue. This is the 14th reported case of this rare entity. It is unique in the degree of involvement, affecting breast parenchyma as well as subcutaneous fat, and in its corresponding dramatic clinical and radiographic manifestations.

Benign and Malignant Male Breast Diseases: Radiologic and Pathologic Correlation.

Male breast disease comprises a wide spectrum of benign and malignant processes. We present the spectrum of diseases encountered at our institution over the past 7 years (2007-2013) and correlate their radiological and histopathological appearances. Gynaecomastia is the most frequently encountered disease due to its association with a variety of causes. Male breast malignancies, though rare, must be considered. The most frequently encountered pathological characteristic is invasive and the predominant histologic subtypes are infiltrating ductal carcinomas.

Impact of the 2013 American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing of invasive breast carcinoma: a focus on tumours assessed as 'equivocal' for HER2 gene amplification by fluorescence in-situ hybridization.

AIMS: The updated 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) human epidermal growth factor receptor 2 (HER2) testing guidelines include changes to HER2 in-situ hybridization (ISH) interpretation criteria. We conducted a retrospective review of a consecutive cohort of primary breast carcinomas to assess the impact of updated guidelines on HER2 classification and laboratory resource utilization, and to characterize the pathobiology of HER2 equivocal tumours. METHODS AND RESULTS: A total of 904 dual-probe HER2/chromosome enumeration probe (CEP17) FISH tests on invasive breast carcinomas were studied. Eighty-five (9.4%) cases had a classification change with the updated guidelines; 66 (7.3%) went from HER2-negative to -equivocal, 15 cases (1.7%) were reclassified as HER2-positive and four cases from HER2-equivocal to -negative. A subset of primary breast cancers, reported initially as HER2-negative but -equivocal by 2013 guidelines, was identified. Traditional pathological factors of this subset were compared to HER2-negative and -positive control cases. The three HER2 groups demonstrated statistically significant differences with respect to prognostic factors, including tumour size, grade and nodal involvement. CONCLUSIONS: The updated HER2 testing guidelines will result in the reclassification of approximately 9.4% of primary breast cancers with uncertainty regarding the clinical impact of this reclassification in the majority of cases. Resource utilization will increase as a result of the recommendation for retesting.

CytoLyt® fixation and decalcification pretreatments alter antigenicity in normal tissues compared with standard formalin fixation.

Immunohistochemistry is used on cell blocks constructed from cytopathology samples fixed in methanol-based fixatives, such as CytoLyt (Cytyc Corp), and on surgical pathology tissues exposed to decalcifying agents, often without technical validation. We evaluated a panel of commonly utilized antibodies in normal tissues exposed to differing preanalytic conditions as follows: CytoLyt fixation, formalin fixation followed by exposure to decalcifying agents (Leica Decalcifier I-10% formic acid or Leica Decalcifier II-5% hydrochloric acid), or standard formalin fixation. Altered expression was observed with several antibodies compared with standard formalin fixation. Specifically, there was absent or near absent expression of thyroid transcription factor 1 (TTF-1), D2-40, and CD20 in CytoLyt-fixed tissues, whereas reduced expression was observed for p63, estrogen receptor, S100 protein, CD3, calretinin, chromogranin, and synaptophysin. Absent or near absent expression of TTF-1 was also observed with exposure to hydrochloric acid, whereas reduced expression was observed for CK5/6, CK7, p63, estrogen receptor, leukocyte common antigen, CD3, CD20, and synaptophysin. Exposure to formic acid had less impact with reduced expression observed for only 3 antibodies (CK8/18, CK7, and TTF-1). The results of this study demonstrate the need to validate immunohistochemical protocols on control tissue treated in the same manner as test tissue, including CytoLyt fixation and exposure of tissue to decalcifying agents.

Human epidermal growth factor receptor 2 testing in primary breast cancer in the era of standardized testing: a Canadian prospective study.

PURPOSE: Therapies that target overexpression of human epidermal growth factor receptor 2 (HER2) rely on accurate and timely assessment of all patients with new diagnoses. This study examines HER2 testing of primary breast cancer tissue when performed with immunohistochemistry (IHC) and additional in situ hybridization (ISH) for negative cases (IHC 0/1+). The analysis focuses on the rate of false-negative HER2 tests, defined as IHC 0/1+ with an ISH ratio ≥ 2.0, in eight pathology centers across Canada. PATIENTS AND METHODS: Whole sections of surgical resections or tissue microarrays (TMAs) from invasive breast carcinoma tissue were tested by both IHC and ISH using standardized local methods. Samples were scored by the local breast pathologist, and consecutive HER2-negative IHC results (IHC 0/1+) were compared with the corresponding fluorescence or silver ISH result. RESULTS: Overall, 711 surgical excisions of primary breast cancer were analyzed by IHC and ISH; HER2 and chromosome 17 centromere (CEP17) counts were available in all cases. The overall rate of false-negative samples was 0.84% (six of 711 samples). Interpretable IHC and ISH scores were available in 1,212 cases from TMAs, and the overall rate of false-negative cases was 1.6% (16 of 978 cases). CONCLUSION: Our observation confirms that IHC is an adequate test to predict negative HER2 status in primary breast cancer in surgical excision specimens, even when different antibodies and IHC platforms are used. The study supports the American Society of Clinical Oncology/College of American Pathologists and Canadian testing algorithms of using IHC followed by ISH for equivocal cases.

Canadian Association of Pathologists-Association canadienne des pathologistes National Standards Committee for High Complexity Testing/Immunohistochemistry: guidelines for the preparation, release, and storage of unstained archived diagnostic tissue sections for immunohistochemistry.

OBJECTIVES: Formalin-fixed, paraffin-embedded unstained archived diagnostic tissue sections are frequently exchanged between clinical laboratories for immunohistochemical staining. The manner in which such sections are prepared represents a type of preanalytical variable that must be taken into account given the growing importance of immunohistochemical assays, especially predictive and prognostic tests, in personalized medicine. METHODS: Recommendations were derived from review of the literature and expert consensus of the Canadian Association of Pathologists-Association canadienne des pathologists National Standards Committee for High Complexity Testing/Immunohistochemistry. RESULTS: Relevant considerations include the type of glass slide on which to mount the unstained sections; the thickness of the tissue sections; the time from slide preparation to testing; the environment, particularly the temperature at which the unstained sections will be maintained prior to testing; the inclusion of on-slide positive control tissue where possible; and whether patient identifier(s) should be included on slide labels. CONCLUSIONS: Clear communication between requesting and releasing laboratories will facilitate the proper preparation of unstained sections and also ensure that applicable privacy considerations are addressed.

Comparison of clinical-pathologic characteristics and outcomes of true interval and screen-detected invasive breast cancer among participants of a Canadian breast screening program: a nested case-control study.

BACKGROUND: Previous analyses of interval breast cancers have been limited because of a lack of control for screening interval length and patient age, failure to restrict the interval group to 'true' intervals, and incomplete descriptions of pathology, adjuvant therapies and clinical outcomes. PATIENTS AND METHODS: A nested case-control study within the population-based Nova Scotia Breast Screening Program was performed. All true interval cases between 1991 and 2004 were identified, matched 1:2 to screen-detected cases (age, screening interval, time period), and compared in terms of pathologic characteristics and adjuvant therapies via logistic regression. Disease-free and overall survival was estimated, controlling for pathology and adjuvant chemotherapy receipt. RESULTS: A total of 241 true interval invasive cases were matched to 481 screen-detected cases. Interval cases were more likely to be > 1 cm (odds ratio [OR] = 1.76; 95% CI, 1.10-2.83), grade 3 (OR = 2.71; 95% CI, 1.49-4.92), and have lymphovascular invasion (OR = 3.06; 95% CI, 1.85-5.07). Interval cases received more adjuvant chemotherapy (OR = 4.37; 95% CI, 3.03-6.30) and radiation (OR = 1.43; 95% CI, 1.02-2.00). The 5-year Kaplan-Meier estimates of disease-free and overall survival rates for true intervals and screens were 0.830 (95% CI, 0.770-0.875) versus 0.926 (95% CI, 0.898-0.947) and 0.860 (95% CI, 0.804-0.901) versus 0.937 (95% CI, 0.910-0.956), respectively. CONCLUSION: True interval breast cancers have more adverse prognostic factors compared with screen-detected cases and, despite receiving more adjuvant chemotherapy, are associated with significantly poorer survival outcomes.

Fine-needle aspiration cytology of mammary fibroadenoma: a comparison of ThinPrep® and cytospin preparations.

Mammary fibroadenoma (FA) is a lesion frequently sampled and diagnosed by fine-needle aspiration (FNA). Accurate cytologic diagnosis of this common benign lesion is important as this can lead to non-surgical, conservative management when breast imaging and clinical examination are concordant. In most instances, a confident diagnosis of FA is possible because of a characteristic cytologic appearance that includes hypercellularity, large epithelial cell groups, staghorn epithelial configurations, stromal fragments, and numerous background stripped nuclei. Nevertheless, FAs can be diagnostically challenging because of shared cytomorphologic features with other benign lesions and low-grade carcinoma. As such, FA is a well-recognized source of false results on FNA cytology. Furthermore, there are reports that newer thin layer cytopreparatory techniques, including the ThinPrep® (TP) system (Hologic Corp., Bedford, MA), alter the appearance of FA on FNA compared to conventional preparations and may compromise accurate cytologic diagnosis.

Flat epithelial atypia on breast needle core biopsy: a retrospective study with clinical-pathological correlation.

There are limited data to guide clinical management when flat epithelial atypia (FEA) is identified in breast needle core biopsies (NCBs). Our objectives were to determine the frequency of malignancy in subsequent breast excisions following NCB diagnosis of FEA, and to characterize the pathological and clinical features of associated tumors. Two hundred and fifty-six breast NCBs from a retrospective search (January 1999-July 2007) were blindly reviewed for FEA/other columnar cell lesions (CCLs). NCBs with co-existing carcinoma were excluded. The study included 211 NCBs: 116 (55%) with CCLs without atypia; 40 (19%) with CCLs with atypical ductal hyperplasia (ADH), 15 (7%) with FEA and 40 (19%) with FEA and ADH; 94 cases had follow-up excisions. Ductal carcinoma in situ and/or invasive carcinoma were present in: 4/26 (15%) excisions with CCLs on NCB, 11/30 (37%) with CCLs + ADH, 1/7 (14%) with FEA alone, and 9/31 (29%) with FEA + ADH. (a) FEA was more frequently seen with ADH, than without ADH in NCBs, (b) FEA and CCLs were more frequently associated with malignancy when with ADH, and (c) tumors excised following NCB diagnosis of FEA+/-ADH had favorable prognostic factors. A conservative excision is warranted following a NCB diagnosis of FEA and ADH, and may be warranted for FEA alone.

Survivin and COX-2 expression in male breast carcinoma.

Male breast carcinoma (Male BC) is a distinct biological subtype of breast cancer. We previously reported an association between 5-year overall survival and strong intratumoral aromatase (ITA) expression in Male BC. In this study, we investigate survivin and COX-2 expression and their relationship to ITA. Clinical data were abstracted for all Male BC patients diagnosed between 1985 and 2005 in Nova Scotia, Canada. Archival tissues were retrieved for tissue microarray (TMA) and immunohistochemistry (IHC). Of 54 Male BCs identified, 39 cases had tissue available for IHC. Survivin expression was noted in 27 cases (69%); 12 nuclear and 26 cytoplasmic while strong COX-2 expression was observed in 14 cases (36%). Cytoplasmic survivin and COX-2 expressions were positively associated with ITA expression. However, survivin and COX-2 expression were not predictive of survival. Additional studies are needed to further elucidate the correlation between cytoplasmic survivin, COX-2 and ITA expression in Male BC considering their potential therapeutic implications.