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Background: The 2013 testing guidelines for determining the human epidermal growth factor receptor 2 (HER2) status include new cutoff points for the HER2/chromosome enumeration probe 17 (CEP17) ratio and the average HER2 copy number per cell, and they recommend using a reflex test with alternative chromosome 17 probes (Ch17Ps) to resolve equivocal HER2 results. This study sought to determine the clinical utility of alternative Ch17Ps in equivocal cases and the effects of equivocal results and/or a change in the HER2 status on patients' outcomes.Methods: The University of Texas MD Anderson Cancer Center database of HER2 dual-probe fluorescence in situ hybridization results from 2000 to 2010 was searched for cases of invasive breast cancer with HER2/CEP17 ratios < 2 and average HER2 copy numbers < 6 per cell. Cases with HER2 copy numbers of 4 to < 6 (the definition of equivocal HER2 results) were analyzed with alternative Ch17Ps for Smith-Magenis syndrome and retinoic acid receptor α genes. Disease-free survival (DFS) and overall survival (OS) were evaluated with respect to the HER2 copy number with multivariate Cox proportional hazards regression.Results: Among the 3630 patients meeting the inclusion criteria, 137 (4%) had equivocal HER2 results. With alternative Ch17Ps, 35 of 57 equivocal HER2 cases (61%) were upgraded to a positive HER2 status, and 22 cases (39%) remained unchanged. The 5-year DFS and OS adjusted hazard ratios (HRs) for copy numbers of 4 to < 6 versus < 4 were 0.6 (95% confidence interval [CI], 0.3-1.2) and 0.5 (95% CI, 0.2-1.0) with P values of .16 and .66, respectively. In comparison with HER2-negative cases, these CIs indicated that equivocal HER2 results were associated with either a protective effect (HR, < 0.5) or no effect (HR, 1.0).Conclusions: These findings rule out a significant deleterious effect of equivocal HER2 results. Alternative Ch17Ps may erroneously upgrade the HER2 status; therefore, they cannot be considered reliable in clinical practice. Cancer 2017;123:1115-1123. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Aims Radiation Therapy Oncology Group 98-04 sought to identify women with 'good risk' ductal carcinoma in situ (DCIS) who receive no significant benefit from radiation. Enrolment criteria excluded close or positive margins and grade 3 disease. To ensure reproducibility in identifying good risk pathology, an optional web based teaching tool was developed and a random sampling of 10% of submitted slides were reviewed by a central pathologist. Methods Submitting pathologists were asked to use the web based teaching tool and submit an assessment of the tool along with the pathology specimen form and DCIS H&E stained slide. Per protocol pathology was centrally reviewed for 10% of the cases. Results Of the 55 DCIS cases reviewed, three had close or positive margins and three were assessed to include grade 3 DCIS, therefore 95% of DCIS cases reviewed were correctly graded, and 89% reviewed were pathologically appropriate for enrolment. Regarding the teaching tool, 13% of DCIS cases included forms that indicated the website was used. One of these seven who used the website submitted DCIS of grade 3. Conclusions Central review demonstrates high pathological concordance with enrolment eligibility, particularly with regard to accurate grading. The teaching tool appeared to be underused. [ABSTRACT FROM AUTHOR]

We evaluated the efficacy of using standard radiologic and histologic criteria to guide the follow-up of patients with lobular carcinoma in situ ( LCIS), lobular neoplasia ( LN), or atypical lobular hyperplasia ( ALH). Patients with high-risk benign lesions diagnosed on biopsy were presented and reviewed in a multidisciplinary clinical management conference from 1 November 2003 through September 2011. Associations between patient characteristics and rates of upgrade were determined by univariate and multivariate logistic models, and times to diagnosis carcinoma were calculated. Of 853 cases reviewed, 124 (14.5%) were lobular neoplasms. In all, 104 patients were clinically and/or radiographically monitored. In 20 patients, who were found to have LN on core biopsy and were recommended to have immediate surgical excision, a more significant lesion was identified in 8 (40%) of the excised specimens. Factors associated with a more significant lesion on excisional biopsy included whether the lobular lesion had been targeted for biopsy and whether the extent of disease involved three or more terminal duct lobular units. Of the 104 patients radiographically and clinically monitored, the median follow-up time was 3.4 years with a range of 0.44-8.6 years. Five patients under surveillance were subsequently diagnosed with breast malignancy (three of the five at a site unrelated to the initial biopsy). Patients with incidental lobular lesions identified on percutaneous core needle biopsy have a small risk of upgrade and may not require an excisional biopsy. Clinical management of low-volume lobular lesions in a multidisciplinary setting is an efficacious alternative to surgical excision when radiologic and histologic characteristics are well-defined. [ABSTRACT FROM AUTHOR]

This review article covers the basic applications of and latest developments in interventional breast sonography (US). For breast masses, US has become the standard for guiding needle biopsy, whether a fine needle or a core biopsy needle is used. US has also become the preferred method for guiding insertion of various localization devices for nonpalpable masses, and US''s intraoperative use for this purpose is expanding. Recently, US has been used to monitor the placement of percutaneous ablation devices, such as radiofrequency ablation needle-electrodes, into breast masses, including carcinomas. US is not indicated for the routine evaluation of microcalcifications. However, on occasion, clusters of microcalcifications without a mass can be visualized on sonograms with sufficient clarity to undertake a US-guided core biopsy if stereotactically guided biopsy cannot be performed for technical reasons. [Copyright &y& Elsevier]

Offers a study of patients with papillary thyroid cancer and the development of malignant pleural effusion during the course of the disease. Methods; Case reports; Treatment and outcome; Finding that malignant pleural effusion may develop many years after the initial diagnosis but is associated with greatly shortened survival time in all cases.

Microglandular adenosis is widely known as a benign breast lesion that can produce a mass. It differs from other types of adenosis by having an infiltrative pattern of growth and glands lacking a myoepithelial layer. Although in every other aspect the cells lining the glands are epithelial, they stain strongly with S100 protein. Most cases of microglandular adenosis are resolved after adequate excision, but more recent data suggest that this lesion may be a precursor for carcinoma, with atypical microglandular adenosis being an intermediate lesion. Carcinomas arising in a background of microglandular adenosis, although they may be low grade, are commonly estrogen and progesterone receptor negative, in contrast to most conventional lowgrade carcinomas unrelated to microglandular adenosis. They also show immunopositivity for S100 protein, similar to microglandular adenosis. Diagnostic problems include differentiating microglandular adenosis from carcinoma and assessing the extent of the carcinoma component. In this review, we discuss the histomorphologic and immunophenotypic characteristic of the spectrum of microglandular adenosis lesions with emphasis on diagnostic features distinguishing microglandular adenosis from well-differentiated carcinoma, in particular, tubular carcinoma, and assessment of surgical margins of excision in such lesions. [ABSTRACT FROM AUTHOR]

Objective: Risk-reducing therapy with selective estrogen receptor (ER) modulators and aromatase inhibitors reduce breast cancer risk. However, the effects are limited to ER-positive breast cancer. Therefore, new agents with improved toxicity profiles that reduce the risk in ER-negative breast cancers are urgently needed. The aim of this prospective, short-term, prevention study was to evaluate the effect of dasatinib, an inhibitor of the tyrosine kinase Src, on biomarkers in normal (but increased risk) breast tissue and serum of women at high risk for a second, contralateral primary breast cancer. Materials and Methods: Women with a history of unilateral stage I, II, or III ER-negative breast cancer, having no active disease, and who completed all adjuvant therapies were eligible. Patients underwent baseline fine-needle aspiration (FNA) of the contralateral breast and serum collection for biomarker analysis and were randomized to receive either no treatment (control) or dasatinib at 40 or 80 mg/day for three months. After three months, serum collection and breast FNA were repeated. Planned biomarker analysis consisted of changes in cytology and Ki-67 on breast FNA, and changes in serum levels of insulin-like growth factor 1 (IGF-1), IGF-binding protein 1, and IGF-binding protein 3. The primary objective was to evaluate changes in Ki-67 and secondary objective included changes in cytology in breast tissue and IGF-related serum biomarkers. Toxicity was also evaluated. Results: Twenty-three patients started their assigned treatments. Compliance during the study was high, with 86.9% (20/23) of patients completing their assigned doses. Dasatinib was well tolerated and no drug-related grade 3 and 4 adverse events were observed. Since only one patient met the adequacy criteria for the paired FNA sample, we could not evaluate Ki-67 level or cytological changes. No significant change in serum biomarkers was observed among the three groups. Conclusion: Dasatinib was well tolerated but did not induce any significant changes in serum biomarkers. The study could not fulfill its primary objective due to an inadequate number of paired FNA samples. Further, larger studies are needed to evaluate the effectiveness of Src inhibitors in breast cancer prevention. [ABSTRACT FROM AUTHOR]

Fine needle aspiration is a minimally invasive, low-morbidity, and cost-efficient technique for the sampling of mediastinal lesions. Additionally, ancillary testing on FNA samples can be used for the refinement of diagnoses and for treatment-related purposes (flow cytometry, cytogenetics, immunohistochemistry, and molecular diagnostics). Mediastinal lesions, however, can show a variety of lineages and morphologic features, giving rise to diagnostic dilemmas. As a result, the differential diagnosis can vary widely and becomes especially challenging due to the smaller sample size on FNA and the variability in component sampling. For appropriate patient management and to determine the correct treatment strategies, accurate pathologic diagnoses are paramount. In this review, we present the cytomorphologic features together with the immunophenotypic findings of mediastinal lesions, with emphasis on the diagnostic challenges and pitfalls in FNA cytology samples, including smears and cell block sections. [ABSTRACT FROM AUTHOR]

We evaluated the detection rates of PAX8 and WT1 immunostaining in 68 (45 as cell blocks, 23 as smears) serous effusion specimens that had a cytologic diagnosis of metastatic carcinoma of ovarian origin. Of the cases, 58 (85%) were positive for PAX8, 56 (82%) were positive for WT1, and 64 (94%) were immunoreactive with either or both markers. Detection rates of PAX8 and WT1 were 85% (44/52) and 92% (48/52), respectively, for metastatic serous carcinoma and 100% (5/5) and 20% (1/5), respectively, for metastatic clear cell carcinoma. Detection rates using cell blocks and smears were 91% and 78%, respectively, with PAX8 and 82% and 83%, respectively, with WT1. We concluded that PAX8 and WT1 had comparable overall detection rates in confirming ovarian origin of malignant effusion. The combination of both markers substantially improved the detection rate. Cell blocks and smears can be used for staining, but a cell block is preferred for PAX8 staining. [ABSTRACT FROM AUTHOR]

One-fifth of breast cancers have the triple-negative phenotype; a good prognostic marker has yet not been described for these tumours. Tumour microarrays from 58 triple-negative patients treated with surgery followed by chemotherapy were analysed for expression of cytokeratin 5/6 (CK5/6), epidermal growth factor receptor (EGFR), vimentin, p63 and cytokeratin 34βE12. The mean patient age was 59.2 years with a follow-up from 39 to 168 months. Clinicopathological variables and survival data were correlated with biomarker expression. The frequency of expression of cytokeratin 5/6, EGFR, vimentin, p63 and 34βE12 was 33%, 65%, 50%, 19% and 85%, respectively. Each of 34βE12, p63, EGFR and T stage significantly correlated with both disease-free survival and overall survival. T stage and 34βE12 were independent predictors of overall survival in a multivariate analysis. Expression of 34βE12 predicts disease-free and overall survival in patients with triple-negative tumours. Additional studies are planned to confirm these initial findings. [ABSTRACT FROM AUTHOR]

Objective: To compare the diagnostic accuracy of ultrasound (US)-guided core needle biopsy (CNB) of breast masses performed with 14-gauge, 16-gauge and 18-gauge needles.Methods: We retrospectively reviewed the charts of 1,112 patients who underwent US-guided breast CNB with 14-gauge, 16-gauge and 18-gauge needles. Cases with surgical excision or a minimum of 2 years of imaging follow-up were included. Rates of sample inadequacy, discordance with surgical or imaging findings and upgrade of DCIS to invasive cancer or high-risk lesion to in situ or invasive cancer were computed for each needle size.Results: The study included 703 CNBs: 203 performed with 14-gauge, 235 with 16-gauge and 265 with 18-gauge needles. There were no significant differences between 14-gauge, 16-gauge and 18-gauge needles in rates of specimen inadequacy (0 %, 0.4 % and 1.9 %, respectively) (p = 0.084); surgical discordance (2.6 %, 2.9 % and 3.8 %) (p = 0.76); imaging discordance (0 %, 0 % and 2 %) (p = 1.0); DCIS upgrade (43 %, 43 % and 36 %) (p = 1.00) or high-risk lesion upgrade (38 %, 25 % and 55 %) (p = 0.49).Conclusion: There was no statistically significant difference in diagnostic accuracy of US-guided CNB of breast masses performed with 14-gauge, 16-gauge and 18-gauge needles.Key Points: • Percutaneous image-guided breast core needle biopsy (CNB) is the standard of care. • Breast CNB with 14-gauge, 16-gauge and 18-gauge needles has similar diagnostic accuracy. • Smaller gauge needles can be confidently used for ultrasound-guided breast CNB. [ABSTRACT FROM AUTHOR]

Background Enhancer of zeste homolog 2 (EZH2), a member of the polycomb group proteins, has been shown to promote cancer progression and breast cancer stem cell (CSC) expansion. Breast CSCs are associated with resistance to radiation in inflammatory breast cancer (IBC), a rare but aggressive variant of breast cancer. In this retrospective study, we examined the clinical role of EZH2 in locoregional recurrence (LRR) of IBC patients treated with radiation. Patients and methods 62 IBC patients who received radiation (7 pre-operative, 55 post-operative) and had adequate follow up to assess LRR were the subject of this study. Positive EZH2 status was defined as nuclear immunohistochemical staining in at least 10% of invasive cancer cells. Association of EZH2 expression with clinicopathologic features were evaluated using the Chi-square statistic and actuarial LRR free survival (LRFS) was determined using the Kaplan-Meier method. Results The median follow-up for this cohort was 33.7 months, and the 5-year overall LRFS rate was 69%. Of the 62 patients, 16 (25.8%) had LRR, and 15 out of 16 LRR occurred in EZH2 expressing cases. Univariate analysis indicated that patients who had EZH2-positive IBC had a significantly lower 5-year locoregional free survival (LRFS) rate than patients who had EZH2-negative IBC (93.3% vs. 59.1%; P = 0.01). Positive EZH2 expression was associated significantly with negative ER status (97.1% in ER- vs 48.1% in ER+; P < 0.0001) and triplenegative receptor status (P =0.0001) and all triple-negative tumors were EZH2-positive. In multivariate analysis, only triple negative status remained an independent predictor of worse LRFS (hazard ratio 5.64, 95% CI 2.19 - 14.49, P < 0.0001). Conclusions EZH2 correlates with locoregional recurrence in IBC patients who received radiation treatment. EZH2 expression status may be used in addition to receptor status to identify a subset of patients with IBC who recur locally in spite of radiation and may benefit from enrollment in clinical trials testing radiosensitizers. [ABSTRACT FROM AUTHOR]

Background National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 suggested the efficacy of adjuvant trastuzumab, even in HER2-negative breast cancer. This finding prompted us to develop a predictive model for degree of benefit from trastuzumab using archived tumor blocks from B-31. Methods Case subjects with tumor blocks were randomly divided into discovery (n = 588) and confirmation cohorts (n = 991). A predictive model was built from the discovery cohort through gene expression profiling of 462 genes with nCounter assay. A predefined cut point for the predictive model was tested in the confirmation cohort. Gene-by-treatment interaction was tested with Cox models, and correlations between variables were assessed with Spearman correlation. Principal component analysis was performed on the final set of selected genes. All statistical tests were two-sided. Results Eight predictive genes associated with HER2 (ERBB2, c17orf37, GRB7) or ER (ESR1, NAT1, GATA3, CA12, IGF1R) were selected for model building. Three-dimensional subset treatment effect pattern plot using two principal components of these genes was used to identify a subset with no benefit from trastuzumab, characterized by intermediate-level ERBB2 and high-level ESR1 mRNA expression. In the confirmation set, the predefined cut points for this model classified patients into three subsets with differential benefit from trastuzumab with hazard ratios of 1.58 (95% confidence interval [CI] = 0.67 to 3.69; P = .29; n = 100), 0.60 (95% CI = 0.41 to 0.89; P = .01; n = 449), and 0.28 (95% CI = 0.20 to 0.41; P < .001; n = 442; Pinteraction between the model and trastuzumab < .001). Conclusions We developed a gene expression–based predictive model for degree of benefit from trastuzumab and demonstrated that HER2-negative tumors belong to the moderate benefit group, thus providing justification for testing trastuzumab in HER2-negative patients (NSABP B-47). [ABSTRACT FROM PUBLISHER]

An abstract of the article "Immediate Assessment of Endobronchial Ultrasound Guided Transbronchial Needle Aspiration (EBUS-TBNA) by Cytotechnologists Helps Optimize Patient Care," by Betsy Jacob, Teresa Joseph, Nour Sneige, Shobha Patel, Tina V. Fanning, Rodolfo Morice and Nancy P. Caraway is presented.

We retrospectively reviewed 25 fine-needle aspiration cases of sclerosing adenosis of the breast in conjunction with histologic features of the paired core-needle biopsy and radiologic findings. The original cytologic diagnoses were benign (n = 19), focally atypical (n = 3), and suspicious for carcinoma (n = 3). The frequent features, although not specific, were low-to-moderate cellularity, bland epithelial cells that focally formed cohesive groups/tubules or occasionally discohesive clusters or individual cells, and fragments of dense fibrous stroma. Some tubules had an angulated configuration. Myoepithelial cells were present in all cases but were scant or absent in small epithelial groups. These cytologic features closely reflected the histologic appearances (ie, compressed and attenuated tubules and sclerotic stroma), but may cause overinterpretation on cytologic smears, especially when angulated tubules, discohesive or individual epithelial cells, scanty myoepithelial cells, and nuclear atypia are noted concurrently. Familiarity with its cytologic features may prevent false-positive diagnosis. Histologic confirmation is recommended for difficult cases. [ABSTRACT FROM AUTHOR]

We retrospectively reviewed 25 fine-needle aspiration cases of sclerosing adenosis of the breast in conjunction with histologic features of the paired coreneedle biopsy and radiologic findings. The original cytologic diagnoses were benign (n = 19), focally atypical (n = 3), and suspicious for carcinoma (n = 3). The frequent features, although not specific, were low-to-moderate cellularity, bland epithelial cells that focally formed cohesive groups/tubules or occasionally discohesive clusters or individual cells, and fragments of dense fibrous stroma. Some tubules had an angulated configuration. Myoepithelial cells were present in all cases but were scant or absent in small epithelial groups. These cytologic features closely reflected the histologic appearances (ie, compressed and attenuated tubules and sclerotic stroma), but may cause overinterpretation on cytologic smears, especially when angulated tubules, discohesive or individual epithelial cells, scanty myoepithelial cells, and nuclear atypia are noted concurrently. Familiarity with its cytologic features may prevent false-positive diagnosis. Histologic confirmation is recommended for difficult cases. [ABSTRACT FROM AUTHOR]

Geyer F C, Lacroix-Triki M, Colombo P-E, Patani N, Gauthier A, Natrajan R, Lambros M B K, Khalifeh I, Albarracin C, Orru S, Marchiò C, Sapino A, Mackay A, Weigelt B, Schmitt F C, Wesseling J, Sneige N & Reis-Filho J S (2012) Histopathology 60, E115-E130 Molecular evidence in support of the neoplastic and precursor nature of microglandular adenosis Aims: Microglandular adenosis (MGA) is a proliferative breast lesion, which has been proposed to be a potential precursor of triple-negative breast cancers. The aims of this study were to determine whether MGAs harbour genetic alterations and if any such genetic aberrations found in MGAs are similar to those found in matched invasive carcinomas. Methods and results: Twelve cases of MGA and/or atypical MGA (AMGA), 10 of which were associated with invasive carcinoma, were evaluated. Immunohistochemical profiling revealed that all invasive carcinomas were of triple-negative phenotype and expressed S100, cytokeratins 8/18 and 'basal' markers. The morphologically distinct components of each case (MGA, AMGA and/or invasive carcinoma) were microdissected and subjected to microarray comparative genomic hybridization. Apart from three typical MGAs, all samples harboured genetic alterations. The percentage of the genome affected by copy number aberrations in MGA/AMGA ranged from 0.5 to 61.9%, indicating varying levels of genetic instability. In three cases, MGA/AMGA displayed copy number aberrations similar to those found in matched invasive components, providing strong circumstantial evidence that MGA may constitute the substrate for the invasive carcinoma development. Conclusions: Our results support the contention that MGA can be a clonal lesion and non-obligate precursor of triple-negative breast cancer. [ABSTRACT FROM AUTHOR]

BACKGROUND: Enhancer of zeste homolog 2 (EZH2), a member of polycomb group proteins, is involved in the regulation of cell cycle progression and has been implicated in various human malignancies, including breast cancer, and also has been associated with aggressive tumor behavior. However, the clinical significance of EZH2 expression in inflammatory breast cancer (IBC), a rare but aggressive type of breast carcinoma, has not been explored. In this retrospective study, the authors examined EZH2 expression in IBC tumors and evaluated the relation between EZH2 expression and patient survival. METHODS: Tissue microarrays of 88 surgically resected IBC tumors were stained immunohistochemically for EZH2, and the authors evaluated the association of EZH2 expression status with clinicopathologic factors and clinical outcome. RESULTS: The median follow-up for the entire cohort was 45.7 months, and the 5-year overall survival (OS) rate was 45%. EZH2 was expressed frequently in IBC tumors (75.7%) and was associated significantly with unfavorable prognostic factors, such as higher tumor grade, negative estrogen receptor status, and triple-negative status (ie, negative for the estrogen, progesterone, and human epidermal growth factor 2 receptors). Univariate survival analysis indicated that patients who had EZH2-positive IBC had a significantly lower 5-year OS rate than patients who had EZH2-negative IBC ( P = .01). In multivariate analysis, only positive EZH2 status remained an independent predictor of worse OS. CONCLUSIONS: EZH2 was expressed frequently in IBC tumors. The current results indicated that EZH2 expression status may be used to identify a subset of patients with IBC who have a relatively worse prognosis. Targeting EZH2 also may provide a novel strategy for improving the clinical outcome of patients with IBC. Cancer 2011;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Context.-The appropriate treatment for patients with pleomorphic lobular carcinoma in situ (PLCIS) is unknown. When diagnosed on core biopsy, excision is recommended; however, management of PLCIS when it involves margins has not been addressed. Objective.-To evaluate the significance of PLCIS that is located close to, or at, a resection margin. Design.-We identified 26 patients with resection specimens containing PLCIS, all of whom were offered chemoprevention and radiation therapy. The margin status in these patients was subdivided as PLCIS cells at the margin without obvious truncation of lesion; PLCIS less than or equal to 1 mm from, but not involving, the margin; PLCIS 1.1 to 2 mm from the margin; and PLCIS at least 2.1 mm from the margin. Results.-Patient age ranged from 35 to 76 years (mean, 58 years), and length of follow-up ranged from 4 to 108 months (mean, 46 months). Six of the 26 patients (23%) received chemoprevention, 4 of 26 patients (15%) received radiation therapy, and 6 of 26 patients (23%) received both. The remaining 10 patients received no further therapy. Pleomorphic lobular carcinoma in situ was at the margin in 6 of the 26 cases (23%), 1 mm from the margin in 7 of 26 cases (27%), 1.1 to 2 mm from the margin in 4 of 26 cases (15%), and was at least 2.1 mm from the margin in 9 of 26 cases (35%). In 1 of the 26 patients, recurrent PLCIS was identified 18 months after initial surgery, for an overall recurrence rate of 3.8%. All other patients were clinically and radiologically free of disease at last follow-up. Conclusions.-This is the first series, to our knowledge, that evaluates margin status in patients with PLCIS and documents recurrence. Recurrent PLCIS was identified at a rate similar to low- or intermediate-grade ductal carcinoma in situ. Therefore, known methods of local control, including surgical excision with negative margins (2 mm), may be the appropriate treatment in these patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: The purposes of this study were to address a persistent controversy as to whether the ER status of a primary tumor remains stable during progression to metastasis and to evaluate the influence of disease course and prior systemic therapy on ER status. METHODS: Breast carcinomas from 227 women with known ER status in both primary tumor and paired metastasis were retrospectively reviewed. ER status was compared between primary and metastatic tumors with respect to metastatic site, interval between two ER assays, and intervening chemotherapy and endocrine therapy. Semiquantitative comparison of ER values was performed for 92 tumor pairs. RESULTS: ER status agreed in 210 (92.5%) patients, including 147 positive and 63 negative. Of the 17 patients (7.5%) with discordant ER status, both negative to positive conversion (n = 7) and positive to negative conversion (n = 10) were observed. ER discordance was not significantly associated with metastatic site (locoregional vs distant), time interval between assays (<5 years vs. ≥5 years), or intervening chemotherapy and endocrine therapy. Semiquantitative levels of ER expression were similar between primary and metastatic tumors. In discordant cases, variations in testing methods and marginal scores were common. CONCLUSIONS: ER status in breast carcinoma is generally stable during progression to metastasis. Preanalytical and analytical variability may contribute to discordance in some cases. Given the importance of ER status for clinical management, ER testing in metastatic breast carcinoma should be repeated, especially for patients whose clinical courses are not compatible with stated ER status. Cancer 2011;117:705-13. [ABSTRACT FROM AUTHOR]

We compared the efficacy of p16 and ProExC immunostaining in detecting cervical intraepithelial neoplasia (CIN) 2+ in 136 formalin-fixed, paraffin-embedded cervical tissue specimens with consensus diagnoses of normal cervix, CIN 1, CIN 2, CIN 3, and carcinoma. Diffuse staining patterns of more than half the thickness of CINs and more than 10% of carcinoma cells were scored as positive. The positivity of p16 and ProExC increased significantly with the severity of cervical lesion (P < .001). For CIN 2+ or CIN 3+, p16 immunostaining was more sensitive (79% for CIN 2+; 90% for CIN 3+) than ProExC immunostaining (67% for CIN 2+; 84% for CIN 3+). ProExC showed higher specificity for CIN 3+ compared with p16. Specimens with p16+/ProExC+ results showed the highest specificity (100% for CIN 2+; 93% for CIN 3+), suggesting that these 2 biomarkers can be used together to distinguish CIN 2/3 from its mimics in cervical biopsy specimens. [ABSTRACT FROM AUTHOR]

Context.—The American Society of Clinical Oncology/ College of American Pathologists (ASCO/CAP) guideline recommendations from January 2007 identified many sources of immunohistochemistry (IHC) testing variation. Objective..—In this current study, we implemented the guidelines and addressed our institution's preanalytic, analytic, and postanalytic variables relating to HER2 testing to improve clinical outcomes. Design..—We evaluated core biopsies performed on breast lesions from 2006 through 2007. Prognostic/predictive markers obtained by IHC were correlated with HER2 fluorescence in situ hybridization (FISH). Preanalytic sources of biopsy testing variation were studied by collecting data on the number of biopsies that needed repeat testing because of inconclusive FISH results. Results..—In the year preceding implementation of the guidelines, the HER2 IHC and FISH concordance was 98%. In an additional 10.8% of cases, the FISH results were inconclusive. When additional material became available to retest the inconclusive cases, the results were informative. Further evaluation of the inconclusive cases revealed that the core needle biopsies received, on average, 4 hours of formalin fixation. After implementation of a minimum 6 hours of fixation and the ASCO/CAP guideline recommendations, the HER2 IHC and FISH concordance was 98.5%. The number of FISH inconclusive cases decreased from 10.8% to 3.4% (a 64% reduction). Repeat estrogen-receptor IHC requests decreased by 40% from 38 in 2006 to 23 in 2007. Conclusions..—We have shown that standardized fixation and adherence to the ASCO/CAP guidelines for HER2 testing has resulted in a greater HER2 IHC and HER2 FISH correlation, decreased numbers of inconclusive FISH cases, decreased repeat estrogen-receptor requests, and financial savings to the Department of Pathology. [ABSTRACT FROM AUTHOR]

The article focuses on a study that compared the prognostic features of inflammatory breast cancer (IBC) and non-IBC locally advanced breast cancer (LABC) to gain insight into the biology of the disease. The authors of the study conducted a retrospective analysis that included a large population of patients with LABC who were treated at the University of Texas M. D. Anderson Cancer Center. It concludes that IBC was associated with a distinctive pattern of early recurrence compared with LABC.

Summary: Background: Gene expression microarrays are being used to develop new prognostic and predictive tests for breast cancer, and might be used at the same time to confirm oestrogen-receptor status and ERBB2 status. Our goal was to establish a new method to assign oestrogen receptor and ERBB2-receptor status to breast carcinoma based on mRNA expression measured using Affymetrix U133A gene-expression profiling. Methods: We used gene expression data of 495 breast cancer samples to assess the correlation between oestrogen receptor (ESR1) and ERBB2 mRNA and clinical status of these genes (as established by immunohistochemical [IHC] or fluorescence in-situ hybridisation [FISH], or both). Data from 195 fine-needle aspiration (FNA) samples were used to define mRNA cutoff values that assign receptor status. We assessed the accuracy of these cutoffs in two independent datasets: 123 FNA samples and 177 tissue samples (ie, resected or core-needle biopsied tissues). Profiling was done at two institutions by use of the same platform (Affymetrix U133A GeneChip). All data were uniformly normalised with dCHIP software. Findings: ESR1 and ERBB2 mRNA levels correlated closely with routine measurements for receptor status in all three datasets. Spearman''s correlation coefficients ranged from 0·62 to 0·77. An ESR1 mRNA cutoff value of 500 identified oestrogen-receptor-positive status with an overall accuracy of 90% (training set), 88% (first validation set), and 96% (second validation set). An ERBB2 mRNA threshold of 1150 identified ERBB2-positive status with the overall accuracy of 93% (training set), 89% (first validation set), and 90% (second validation set). Reproducibility of mRNA measurements in 34 replicate experiments was high (correlation coefficient 0·975 for ESR1, 0·984 for ERBB2). Interpretation: Amounts of ESR1 and ERBB2 mRNA as measured by the Affymetrix GeneChip reliably and reproducibly establish oestrogen-receptor status and ERBB2 status, respectively. [Copyright &y& Elsevier]

A 44-year-old man was referred for a right chest nodule of 3 months duration. A ‘benign’ nodule had been excised from this location 8 years prior. On examination, palpable nodes were noted in the right axilla. Radiographic studies were significant only for right axillary lymphadenopathy. Histologically, a nodular dermal proliferation composed of poorly differentiated epithelioid cells in nests and focally forming ducts with pseudopapillary architecture comprised the primary tumor. Features of a clear cell hidradenoma were noted focally. Immunohistochemical (IHC) analysis revealed reactivity for HMW cytokeratins, CK5 and CK7, p53, p63, CEA (focal), androgen receptor, EGFR, estrogen receptor (ER), MUC5AC, and strong/diffuse membranous staining for Her-2/ neu. Negative stains included villin, TTF-1, CDX2, S-100 protein, vimentin, gross cystic disease fluid protein 15 (GCDFP-15), mammoglobulin, and MUC2. A wide local excision and axillary node dissection was performed. Metastatic tumor involved nine of 28 nodes. Interphase fluorescence in situ hybridization (FISH) demonstrated chromosomal amplification of the Her-2/neu locus within the tumor and a nodal metastasis. The patient has completed adjuvant and radiotherapy, including trastuzumab, and is asymptomatic. We believe this to be the first demonstration of Her-2/neu amplification in a malignant skin adnexal tumor. In analogy to breast carcinoma, these findings suggest the applicability of trastuzumab for patients with metastatic adnexal carcinomas demonstrating Her-2/neu amplification. [ABSTRACT FROM AUTHOR]

It has been suggested that expression of anti-apoptotic proteins such as Bcl-2 or BAG-1 may confer cellular resistance to chemotherapy. A corollary of this hypothesis is that expression of these proteins may predict clinical response to treatment and that Bcl-2- or BAG-1-positive cells may selectively be enriched in postchemotherapy tissue specimens. The goal of this exploratory pilot study was to assess these two predictions by using immunohistochemistry in 29 paired pre- and postchemotherapy breast tissue specimens obtained from patients who underwent preoperative doxorubicin-based chemotherapy. All breast cancers expressed BAG-1 protein, and, in individual tumors, 40-100% of neoplastic cells stained positive for this protein. Homogenous cytoplasmic staining was typically observed, though neoplastic cells also showed nuclear staining in many specimens. We found no correlation between prechemotherapy expression of BAG-1 and subsequent pathological response to cytotoxic therapy. Paired pre- and posttreatment specimens showed similar levels of BAG-1 expression when residual tumor could be assessed. Bcl-2 was expressed in 55% of cancers and was localized to the cytoplasm. Absence of Bcl-2 expression in prechemotherapy specimens was associated with more frequent complete pathological response (58% vs. 20%; p = 0.04). However, similar to BAG-1, no difference between pre- and posttherapy expression of Bcl-2 was observed in neoplastic cells in paired tissue specimens. These observations suggest that BAG-1 contributes an important cellular function to breast epithelial cells, which is reflected by its ubiquitous expression in these tissues. However, it does not appear to determine response to doxorubicin-based chemotherapy. In contrast, lack of Bcl-2 expression was associated with a higher probability of complete pathological response to doxorubicin-based chemotherapy. [ABSTRACT FROM AUTHOR]

: PurposeTo compare rates of locoregional recurrence (LRR) after mastectomy, doxorubicin-based chemotherapy, and radiation with those of patients receiving mastectomy and doxorubicin-based chemotherapy without radiation and to determine predictors of LRR after postmastectomy radiation.: MethodsKaplan-Meier freedom-from-LRR rates were calculated for 470 patients treated with mastectomy, doxorubicin-based chemotherapy, and postmastectomy radiation in five single-institution clinical trials. The LRR rates in these patients were compared to previously reported rates in 1031 patients treated without radiation in the same trials.: ResultsMedian follow-up was 14 years. Irradiated patients had significantly less favorable prognostic factors for LRR than did unirradiated patients. Despite this, in all subsets of node-positive patients, postmastectomy radiation led to lower rates of LRR. This included patients with T1 or T2 tumors and one to three positive nodes (10-year LRR rates of 3% vs. 13%, p = 0.003). Multivariate analysis of LRR for patients with this stage of disease revealed that no radiation, close/positive margins, gross extracapsular extension, and dissection of <10 nodes predicted for increased LRR (hazard ratios 6.25, 4.61, 3.27, and 2.66, respectively). Significant predictors of LRR for patients treated with postmastectomy radiation were higher number and ≥20% positive nodes, larger tumor size, lymphovascular space invasion, and estrogen receptor (ER)-negative disease. Recursive partitioning analysis revealed ER-negative status to be the most powerful discriminator of LRR in irradiated patients.: ConclusionsPostmastectomy radiation decreases LRR for patients with breast cancer, including those with Stage II breast cancer and one to three positive lymph nodes. [Copyright &y& Elsevier]

Purpose: To compare the pathologic factors associated with postmastectomy locoregional recurrence (LRR) in breast cancer patients not receiving radiation who were treated with neoadjuvant chemotherapy (NEO) vs. adjuvant chemotherapy (ADJ).Methods and Materials: We retrospectively analyzed the rates of LRR of subsets of women treated in prospective trials who underwent mastectomy and received chemotherapy but not radiation. These trials were designed to answer chemotherapy questions. There were 150 patients in the NEO group and 1031 patients in the ADJ group. In the NEO group, 55% had clinical Stage IIIA or higher vs. 9% in the ADJ group (p <0.001, chi-square test).Results: Despite the more advanced clinical stage in the NEO group, the pathologic size of the primary tumor and the number of positive lymph nodes (+LNs) were significantly less in the NEO group than in the ADJ group (p <0.001 for both comparisons). However, the 5-year actuarial LRR rate was 27% for the NEO group vs. 15% for the ADJ group (p = 0.001, log—rank). The 5-year risk for LRR was higher in the NEO patients for all pathologic tumor sizes: 0–2 cm (18% vs. 8%, p = 0.011), 2.1–5 cm (36% vs. 15%, p <0.001), and >5 cm (46% vs. 28%, p = 0.028). The risk of LRR by the number of +LNs was similar in the NEO and ADJ groups, except for the subset of patients with ≥4 +LNs (53% vs. 23%, p <0.001). The rates of LRR in the patients with primary tumors measuring ≤2.0 cm and 1–3 +LNs were similar in both groups. However, for the patients with a pathologic tumor size of 2.1–5.0 cm and 1–3 +LNs, the LRR was higher in the NEO group than in the ADJ group (30% vs. 15%, p = 0.016). Most failures in this NEO subgroup had clinical Stage III disease. In a subset of NEO and ADJ patients matched for clinical stage, no significant differences were found in the rates of LRR according to primary tumor size and number of +LNs when these variables were analyzed independently. Again, however, differences were found in the subgroup of patients with tumors pathologically measuring 2.1–5.0 cm with 1–3 +LNs (32% NEO vs. 8% ADJ, p = 0.030).Conclusion: The rates of postmastectomy LRR for any pathologic tumor size are higher for patients treated with initial chemotherapy than for patients treated with initial surgery. Radiotherapy should be offered to all patients with ≥4 +LNs, tumor size >5 cm, or clinical Stage IIIA or greater disease, regardless of whether they receive neoadjuvant or postoperative chemotherapy. The information assessing LRR rates in patients with clinical Stage II disease who receive neoadjuvant chemotherapy, particularly if 1–3 lymph nodes remain pathologically involved, is insufficient to determine whether these patients should receive radiotherapy. [Copyright &y& Elsevier]

Background: Uncontrolled studies have reported encouraging outcomes for patients with high-risk primary breast cancer treated with high-dose chemotherapy and autologous hematopoietic stem cell support. We conducted a prospective randomized trial to compare standard-dose chemotherapy with the same therapy followed by high-dose chemotherapy.Patients and Methods: Patients with 10 or more positive axillary lymph nodes after primary breast surgery or patients with four or more positive lymph nodes after four cycles of primary (neoadjuvant) chemotherapy were eligible. All patients were to receive eight cycles of 5-fluorouracil, doxorubicin (Adriamycin), and cyclophosphamide (FAC). Patients were stratified by stage and randomly assigned to receive two cycles of high-dose cyclophosphamide, etoposide, and cisplatin with autologous hematopoietic stem cell support or no additional chemotherapy. Tamoxifen was planned for postmenopausal patients with estrogen receptor-positive tumors and chest wall radiotherapy was planned for all. All P values are from two-sided tests.Results: Seventy-eight patients (48 after primary surgery and 30 after primary chemotherapy) were registered. Thirty-nine patients were randomly assigned to FAC and 39 to FAC followed by high-dose chemotherapy. After a median follow-up of 6.5 years, there have been 41 relapses. In intention-to-treat analyses, estimated 3-year relapse-free survival rates were 62% and 48% for FAC and FAC/high-dose chemotherapy, respectively (P =.35), and 3-year survival rates were 77% and 58%, respectively (P =.23). Overall, there was greater and more frequent morbidity associated with high-dose chemotherapy than with FAC; there was one septic death associated with high-dose chemotherapy.Conclusions: No relapse-free or overall survival advantage was associated with the use of high-dose chemotherapy, and morbidity was increased with its use. Thus, high-dose chemotherapy is not indicated outside a clinical trial. [ABSTRACT FROM AUTHOR]

A quiz concerning the pathology of the disease of a 40-year-old African American woman with ill-defined cystic breast mass is presented.

The article discusses the author's response to the issue on fine-needle aspiration (FNA) materials for microarrays. It states that there is current information and literature presenting microarray data derived from FNA samples with the help of the Ribonucleic acid (RNA) solution. It proposes that a researcher should also take into account every aspect when dealing with RNA.