Translational Potential of Fluorescence Polarization for Breast Cancer Cytopathology.

Breast cancer is the most common malignancy in women. The standard of care for diagnosis involves invasive core needle biopsy followed by time-consuming histopathological evaluation. A rapid, accurate, and minimally invasive method to diagnose breast cancer would be invaluable. Therefore, this clinical study investigated the fluorescence polarization (Fpol) of the cytological stain methylene blue (MB) for the quantitative detection of breast cancer in fine needle aspiration (FNA) specimens. Cancerous, benign, and normal cells were aspirated from excess breast tissues immediately following surgery. The cells were stained in aqueous MB solution (0.05 mg/mL) and imaged using multimodal confocal microscopy. The system provided MB Fpol and fluorescence emission images of the cells. Results from optical imaging were compared to clinical histopathology. In total, we imaged and analyzed 3808 cells from 44 breast FNAs. Fpol images displayed quantitative contrast between cancerous and noncancerous cells, whereas fluorescence emission images showed the morphological features comparable to cytology. Statistical analysis demonstrated that MB Fpol is significantly higher (p < 0.0001) in malignant vs. benign/normal cells. It also revealed a correlation between MB Fpol values and tumor grade. The results indicate that MB Fpol could provide a reliable, quantitative diagnostic marker for breast cancer at the cellular level.

Savi-Scout Radar Localization: Transitioning From the Traditional Wire Localization to Wireless Technology for Surgical Guidance at Lumpectomies.

Breast-conserving surgery or lumpectomy requires localization of the lesion prior to surgery, which is traditionally accomplished by imaging-guided wire localization. Over the last decade, alternatives to wire localization have emerged. This work reviews the literature on one such wireless technology, SaviScout radar (SSR) system, and shares our experience with using this technology for presurgical tumor localization. The SSR surgical guidance system is non-radioactive. The radiologist implants a reflector device in the breast under mammography or ultrasound guidance at any time prior to surgery. The placement of this reflector can be confirmed from the cadence of a handheld percutaneous probe of a handpiece and console system. Results from several studies show that the surgical outcomes from SSR and wire-localization are similar. SSR provides operational advantages as the scheduling for reflector placement by radiologists is decoupled from surgery, but at an increased cost compared to wire-localization.

Vitamin D receptor gene polymorphisms in chronic kidney disease Egyptian children: effect on biochemical markers of bone mineral disorders.

INTRODUCTION: The aim of this study was to assess the association between four vitamin D receptor (VDR) single nucleotide polymorphisms BsmI (rs1544410), ApaI (rs7975232), FokI (rs2228570) and TaqI (rs731236) and the susceptibility to chronic kidney disease (CKD) in Egyptian children and to evaluate their association with mineral status in these patients. MATERIAL AND METHODS: The current study included 305 patients with CKD and 100 apparently healthy children. We measured the serum vitamin D (VD), para-thyroid hormone (PTH) level and fibroblast growth factor 23 (FGF-23) levels by ELISA method. The genotyping of the four VDR gene variants was carried out by PCR-RFLP technique. RESULTS: The TaqI AG & the BsmI TT genotypes were associated with a significantly higher risk of CKD. The expression of 25-OH D serum level was decreased in patients with TaqI GG & AG genotypes groups and in patients with BsmI TT genotype group The expression of PTH serum level was increased in patients with BsmI CT genotype group. The expression of FGF-23 serum level was increased in patients with Taq1 AG genotype group. We found 3 specific haplotypes; AGCA, AGCC and GGCA for healthy controls. CONCLUSIONS: Our study showed an association between VDR TaqI, BsmI polymorphisms and the susceptibility to CKD. The existence of VDR vari-ants affected the protein expression of VD, FGF-23 and PTH. The AGCA, AGCC and GGCA haplotypes were considered as protec-tive factors against the development of renal nephropathy in our population.

Detection of exosomal miR-18a and miR-222 levels in Egyptian patients with hepatic cirrhosis and hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is known to be the second leading cause of cancer-related mortality worldwide. For improving the prognosis as well as reducing the rate of mortality, early diagnosis of HCC is a must. AIMS: This study was conducted to assess the ability of the serum expression of exosomal miR-18a and miR-222 to differentiate and diagnose patients with HCC, patients with liver cirrhosis, and healthy controls. METHODS: This study included 51 patients with liver cirrhosis, 51 patients with HCC on top of hepatitis C virus (HCV) infection, and 50 healthy controls. RESULTS: miR-18a and miR-222 were assessed using reverse transcription-polymerase chain reaction. MiR-18a and miR-222 levels were significantly higher in the liver cirrhosis and HCC groups than the control group (p ˂ 0.001). However, no statistically significant difference was found between patients with HCC and liver cirrhosis (p = 0.4 for miR-18a and p = 0.1 for miR-222). ROC curve analyses to evaluate the diagnostic performances of the two miRNAs as important noninvasive diagnostic markers revealed a best cutoff value of 2 for miR-18a to differentiate between liver cirrhosis, HCC, and healthy controls. And for mir-222, a cutoff value of 1.7 and 1.9 showed the highest specificity for discrimination between liver cirrhosis, HCC, and healthy controls, respectively. Moreover, logistic regression model revealed that miR-18a expression was independent predictive factor in HCC patients (p = 0.004), while miR-222 expression was independent predictive factor in liver cirrhosis patients (p < 0.001). CONCLUSION: miR-18a and miR-222 were significantly discriminative markers between patients with liver cirrhosis and HCC and healthy individuals. Therefore, they have a prognostic rather than a diagnostic value. Moreover, miR-18a and miR-222 could be useful in identifying liver injuries, including fibrosis and cirrhosis.

Deconvolution microscopy: A platform for rapid on-site evaluation of fine needle aspiration specimens that enables recovery of the sample.

CONTEXT: Rapid on-site evaluation (ROSE) optimises the performance of cytology, but requires skilled handling, and smearing can make the material unavailable for some ancillary tests. There is a need to facilitate ROSE without sacrificing part of the sample. OBJECTIVE: We evaluated the image quality of inexpensive deconvolution fluorescence microscopy for optically sectioning non-smeared fine needle aspiration (FNA) tissue fragments. DESIGN: A portion of residual material from 14 FNA samples was stained for 3 min in Hoechst 33342 and Sypro™ Red to label DNA and protein respectively, transferred to an imaging chamber, and imaged at 200× or 400× magnification at 1 micron intervals using a GE DeltaVision inverted fluorescence microscope. A deconvolution algorithm was applied to remove out-of-plane signal, and the resulting images were inverted and pseudocoloured to resemble H&E sections. Five cytopathologists blindly diagnosed 2 to 4 representative image stacks per case (total 70 evaluations), and later compared them to conventional epifluorescent images. RESULTS: Accurate definitive diagnoses were rendered in 45 (64%) of 70 total evaluations; equivocal diagnoses (atypical or suspicious) were made in 21 (30%) of the 70. There were two false positive and two false negative "definite" diagnoses in three cases (4/70; 6%). Cytopathologists preferred deconvolved images compared to raw images (P < 0.01). The imaged fragments were recovered and prepared into a ThinPrep or cell block without discernible alteration. CONCLUSIONS: Deconvolution improves image quality of FNA fragments compared to epifluorescence, often allowing definitive diagnosis while enabling the ROSE material to be subsequently triaged.

Ultrasound Imaging Morphology is Associated with Biological Behavior in Invasive Ductal Carcinoma of the Breast.

OBJECTIVES: Ultrasound (US) is commonly used for diagnostic evaluation of breast lesions. The objective of this study was to investigate the association between US imaging morphology from routine radiologists' interpretation and biological behavior such as receptor status and tumor grade determined from histopathology in invasive ductal carcinoma (IDC). MATERIAL AND METHODS: This retrospective study included 453 patients with pathology-verified diagnosis of IDC who had undergone US imaging and had surgery over a 5-year period. US and surgical pathology reports were reviewed and compiled. Correlation analyses and age-adjusted multivariable models were used to determine the association between US imaging morphology and receptor status, tumor grade, and germ line mutation of the breast cancer genes (BRCA1 and BRCA2). The odds ratio (OR), area under receiver operating characteristic curve (AUC), and 95% confidence intervals (CI) were obtained. RESULTS: The likelihood for high-grade cancer increased with size (OR: 1.066; CI: 1.042-1.091) and hypo-echogenicity (OR: 2.044; CI: 1.337-3.126), and decreased with angular or spiculated margins (OR: 0.605; CI: 0.393-0.931) and posterior acoustic shadowing (OR: 0.352; CI: 0.238-0.523). These features achieved an AUC of 0.799 (CI: 0.752-0.845) for predicting high-grade tumors. The likelihood for Estrogen Receptor-positive tumors increased with posterior acoustic shadowing (OR: 3.818; CI: 2.206-6.607), angulated or spiculated margins (OR: 2.596; CI: 1.159-5.815) and decreased with US measured tumor size (OR: 0.959; CI: 0.933-0.986) and hypoechoic features (OR: 0.399; CI: 0.198- 0.801), and achieved an AUC of 0.787 (CI: 0.733-0.841). The likelihood for Progesterone Receptor-positive tumors increased with posterior acoustic shadowing (OR: 2.732; CI: 1.744-4.28) and angulated or spiculated margins (OR: 2.618; CI: 1.412-4.852), and decreased with US measured tumor size (OR: 0.961; CI: 0.937-0.985) and hypoechoic features (OR: 0.571; CI: 0.335-0.975), and achieved an AUC of 0.739 (CI: 0.689-0.790). The likelihood for Human epidermal growth factor receptor 2-positive tumors increased with heterogeneous echo texture (OR: 2.141; CI: 1.17- 3.919) and decreased with angulated or spiculated margins (OR: 0.408; CI: 0.177-0.944), and was marginally associated with hypoechoic features (OR: 2.101; CI: 0.98-4.505) and circumscribed margins (OR: 4.225; CI: 0.919-19.4). The model with the aforementioned four US morphological features and achieved an AUC of 0.686 (CI: 0.614-0.758). The likelihood for triple-negative breast cancers increased with hypo-echogenicity (OR: 2.671; CI: 1.249-5.712) and decreased with posterior acoustic shadowing (OR: 0.287; CI: 0.161-0.513), and achieved an AUC of 0.739 (CI: 0.671- 0.806). No statistical association was observed between US imaging morphology and BRCA mutation. CONCLUSION: In this study of over 450 IDCs, significant statistical associations between tumor grade and receptor status with US imaging morphology were observed and could serve as a surrogate imaging marker for the biological behavior of the tumor.

Colposcopic endocervical brushing cytology appears to be more sensitive than histologic endocervical curettage for detecting endocervical adenocarcinoma.

INTRODUCTION: Colposcopic endocervical brushing cytology (CEB) is more sensitive than endocervical curettage (ECC) for detecting squamous intraepithelial lesions. There are no data on performance of CEB for detecting endocervical adenocarcinoma. MATERIALS AND METHODS: A total of 151 patients were identified in a word search for "endocervical adenocarcinoma" in surgical pathology reports from January 2007 to June 2019. To measure sensitivity, reports of CEB or ECC samples within 1 year preceding the first surgical pathology diagnosis of at least endocervical adenocarcinoma in situ (AIS+) were examined. Specificity was measured in a cohort in which at least atypical glandular cells (AGC+) was reported in CEB or ECC. RESULTS: Seven CEB preceding diagnosis of AIS were identified: 6 of 7 were positive or suspicious for AIS+. One of 7 was negative and it was negative on re-review. Three of 6 positive CEB cases used cell blocks with immunohistochemistry. Seventy ECC samples preceding diagnosis of AIS were identified: 40 of 70 were diagnosed as AGC+. The sensitivities of CEB and ECC for detecting AIS+ at a threshold of AGC+ are 86% and 57% (too few patients for statistics), respectively. For specificity, 12 of 18 CEB and 9 of 25 ECC reports with AGC+ were false positive by follow-up surgical pathology. The specificities of CEB and ECC are 99.4% and 99.9%, respectively. CONCLUSION: Sensitivity of CEB for detecting AIS+ (86%) is at least as high as ECC (57%). Specificity of CEB is similar to ECC. Addition of a cell block to CEB may be useful. CEB appears to be an appropriate test for follow-up of atypical glandular cells reported on Papanicolaou tests.

Molecular analysis of a rare case of low-grade primary peritoneal serous carcinoma in a male.

Primary peritoneal serous carcinomas (PPSC) are exceedingly rare in male patients. Only a few cases were reported, and mostly with the limited immunophenotypical characterization. No molecular analysis of PPSC in males has been previously performed. We here describe another case of PPSC in a male patient. A comprehensive molecular analysis of the tumor revealed SF3B1 gene mutation as a possible driver.

IRS2 mutations linked to invasion in pleomorphic invasive lobular carcinoma.

Pleomorphic invasive lobular carcinoma (PILC) is an aggressive variant of invasive lobular breast cancer that is associated with poor clinical outcomes. Limited molecular data are available to explain the mechanistic basis for PILC behavior. To address this issue, targeted sequencing was performed to identify molecular alterations that define PILC. This sequencing analysis identified genes that distinguish PILC from classic ILC and invasive ductal carcinoma by the incidence of their genomic changes. In particular, insulin receptor substrate 2 (IRS2) is recurrently mutated in PILC, and pathway analysis reveals a role for the insulin receptor (IR)/insulin-like growth factor-1 receptor (IGF1R)/IRS2 signaling pathway in PILC. IRS2 mutations identified in PILC enhance invasion, revealing a role for this signaling adaptor in the aggressive nature of PILC.

Klotho G-395A gene polymorphism: impact on progression of end-stage renal disease and development of cardiovascular complications in children on dialysis.

BACKGROUND: Klotho G-395-A gene polymorphism may impact children with end-stage renal disease (ESRD). We investigated the relevance of Klotho G-395-A on ESRD development and progression, and its relationship with evolution of cardiovascular complications in pediatric dialysis patients. METHODS: Fifty-five children with chronic kidney disease (CKD) and seventy healthy children were genotyped for Klotho G-395A. RESULTS: Incidence of GA/AA genotypes and A allele were higher in ESRD patients compared with controls (54.5 vs. 7.1%, P < 0.001; 30.9 vs. 13.6%, P = 0.001, respectively). Also, children with GA/AA genotypes were 15.6 times more likely to develop ESRD than with GG genotype (95% CI 5.4-44.7, P < 0.001). A allele carriers have 2.8 times higher risk of developing ESRD than those with G allele (95% CI 1.5-5.35, P = 0.001). Also, the A allele could be considered a predictor of cardiovascular disease (CVD), as carriers have 161 times higher risk of cardiovascular complications than non-carriers (95% CI 21-1233, P < 0.001). All ESRD patients with CVD presented with left ventricular hypertrophy (LVH) and the frequency of A allele was significantly higher among ESRD children with LVH, whereas G allele frequency was significantly higher among ESRD children without LVH. CONCLUSIONS: The A allele of the G-395A Klotho gene polymorphism shows a significantly higher frequency among children with CKD and those with CVD and LVH. This mutant allele could be used as a risk marker for the development of ESRD as well as a predictor of CVD in these children.

Impact of Apo E gene polymorphism on HCV therapy related outcome in a cohort of HCV Egyptian patients.

The functional apolipoprotein E (Apo E) gene polymorphism could be used as a determinant of outcome of HCV infection. This study aimed to demonstrate the impact of Apo E genotype on the response to HCV combined therapy. MATERIAL AND METHODS: The study has been implemented on 125 individuals with persistent HCV infection and 120 cases with sustained virologic response (SVR). All participants were genotyped for ApoE gene polymorphism by a real-time quantitative PCR (qPCR). RESULTS: Statistically significant differences were demonstrated regarding the Apo E genotypes between the two groups (P-value < .001) where the frequency of E3E3 was significantly higher among the chronic HCV-patients while E3E4 and E4E4 genotypes frequencies were higher among the SVR-subjects group and E3E3 genotype was associated with increased risk of chronicity (OR 4.7; 95% CI 1.9-12.1, P-value < .001). Moreover, There were statically significant differences regarding E3 and E4 alleles frequencies, where E3 allele display a higher frequency among the chronic HCV-patient group while the SVR-subjects group showed higher frequency of E4 allele and the carriers of E3 allele have 1.4 times more risk to develop chronicity than those with E4 allele (OR 1.4; 95% CI 1.0-2.0, P-value < .05). Meanwhile the protective E2 allele was absent in all infected participants. CONCLUSION: This study supports the hypothesis of the protective impact of Apo E4 allele that favors viral clearance of HCV infection and its recovery after combined therapy, while the Apo E3 allele is considered as a particular risk factor for the chronicity in HCV patients and resistance to therapy. Whereas the Apo E2 allele confers a resistance to HCV infection at a time of exposure.

Fas/Fas Ligand pathways gene polymorphisms in pediatric renal allograft rejection.

BACKGROUND: An essential milestone in pediatric transplantation is to find noninvasive biomarkers to monitor acute rejection (AR). In this retrospective (Case-control) study, we examined the role of Fas -670A/G and Fas Ligand (FasL) -843C/T gene polymorphisms in allograft nephropathy in pediatric renal transplant recipients. METHODS: In 47 pediatric kidney transplant recipients and 20 healthy controls, Fas -670A/G and FasL -843C/T gene polymorphisms as well as serum soluble Fas Ligand level (sFasL) were measured. RESULTS: Serum sFasL levels were significantly higher in transplant recipients children than that in controls (548.25±298.64pg/ml vs 143.17±44.55pg/ml, p=0.0001). There was no significant difference between patients with AR and those without AR in regards to serum sFasL levels (567.70±279.87pg/ml vs 507.85±342.80pg/ml, p=0.56). Fas -670A/G genotypes or alleles were not significantly different between controls and transplant recipients and among transplant recipients with and without AR. (P>0.05 for all). FasL -843C/T genotypes were not different between transplant recipients and controls and among transplant recipients with and without AR (P>0.05 for all). However, Frequency of C allele in transplant patients was significantly higher than that in the control group (44.68% vs 25%, P=0.03). FasL -843C/T alleles were significantly different between patients with and without AR (P=0.03). The percentages of C allele were higher in children with AR (58.82% vs 36.67%). We found that serum FasL and serum creatinine were variables that were independently associated with AR. CONCLUSION: This study suggests that FasL gene polymorphisms in peripheral blood might be accurate in detecting cellular AR.

Coagulation, thrombophilia and patency of arteriovenous fistula in children undergoing haemodialysis compared with healthy volunteers: a prospective analysis.

UNLABELLED: This study aimed to assess whether markers of coagulation, fibrinolysis or thrombophilia are increased in children on haemodialysis compared with controls and whether measurement of any of these factors could help to identify patients at an increased risk of arteriovenous fistula (AVF) occlusion. Blood samples were taken from 55 children immediately before a session of haemodialysis and from 20 healthy volunteers. Thrombin-antithrombin (TAT), D-dimer, plasmin-antiplasmin (PAP) and anticardiolipin immunoglobulin G (ACA-Ig G) were measured by ELISA. Factor V Leiden mutation (G1691A) was determined by gene polymorphism [restriction fragment length polymorphism (RFLP)]. Determination of the patency of the AVF was prospectively followed up for a minimum of 4 years or until the AVF was nonfunctioning. Fifty-five patients were studied with a median follow-up of 659 days (range 30-1670 days). A significant increase was found in the levels of D-dimer, PAP and ACA-Ig G in haemodialysis patients with thrombosed and nonthrombosed native AVFs vs. CONTROLS: There was a significant difference between both chronic haemodialysis patients with thrombosed and nonthrombosed native AVF with regard to ACA-IgG levels. At 1 year follow-up, primary patency was 61.4% (27 patients). In multivariate analysis, D-dimer was inversely associated with secondary patency.Thrombophilia may predispose children with end stage renal disease to access failure. The promising finding is that in children on haemodialysis, D-dimer levels were increased and inversely correlated with secondary patency. Further evaluation is required into the possible role of D-dimer as a biomarker of AVF occlusion.

Diagnosis of Metaplastic Breast Carcinoma: Keratin OSCAR Versus Other Cytokeratins.

Metaplastic breast carcinoma (MBC) is a heterogenous group of tumors that diverge from conventional glandular differentiation. The metaplastic component can be focal or may be present purely posing diagnostic challenges. Since MBC may show focal immunostaining or may even be negative for some cytokeratins (CK), different CKs are often needed to prove their epithelial origin. OSCAR is a relatively new broad-spectrum anti-CK antibody. Thirty MBC cases diagnosed at our institution were retrieved, including 7 spindle cell carcinomas. Representative slides were immunostained for CK-OSCAR, CK-AE1/AE3, CAM5.2, CK-903, and CK5/6. Nineteen spindle cell lesions were used as controls, including 6 malignant and 10 borderline phyllodes tumor, 1 inflammatory pseudotumor, 1 solitary fibrous tumor, and 1 nodular fasciitis case. All 30 cases (100%) of metaplastic carcinomas were positive for CK-OSCAR, compared with 27/30 (90%, P=0.076) for CK-AE1/AE3, 21/30 (70%, P≤0.01) for CK-903, 19/30 (63.3%, P≤0.01) for CAM5.2, and 15/30 (50%, P≤0.01) for CK5/6. All control cases were negative for CK-OSCAR. All 7 spindle cell carcinomas were also positive for CK-OSCAR (100%) compared with 6/7 (85.7%) for CK-AE1/AE3, 4/7 (57%) for CK-903, 3/7 (42.8%) for CAM5.2, and 2/7 (28.5%) for CK5/6. Our data show that CK-OSCAR is more sensitive than other individual CKs in diagnosing MBC. Coupled with high specificity, CK-OSCAR may potentially be used in lieu of a panel of CKs to identify the epithelial origin of these tumors, especially in spindle cell tumors. This is particularly useful in limited core biopsy specimens, to help guide treatment and simultaneously lower testing costs.

Interactive Effects of Immunoglobulin Gamma and Human Leucocyte Antigen Genotypes on Response to Interferon Based Therapy of Hepatitis C Virus.

AIM: We examined the role that immunoglobulin GM 23 and KM allotypes-genetic markers of γ and κ chains, respectively-play in response to treatment of hepatitis C virus (HCV) infection in Egyptian patients. MATERIAL AND METHODS: A total of 120 persons who had responded to HCV treatment and 125 with persistent HCV infection were genotyped for the presence of GM23 and KM determinants. HLA -C genotyping was also done. RESULTS: Association of GM 23+ and KM3 was significantly associated with non response to treatment (P < 0.0001). Individuals who lacked this GM genotype (but were positive for KM1,2 and 3) were likely to respond to treatment (P=0.045). Association of heterozygous GM23 (+/-) with KM 1,2 and 3 or KM3 alone was significantly associated with SVR (P = 0.001) and (P = 0.0001) respectively. Particular combinations of HLA and GM genotypes were associated significantly with the response to HCV treatment. The combination of HLAC2C2 and GM23+ was associated with persistence of infection (P = 0.027) while the association of HLAC2C2 and heterozygous GM23+/- was associated with SVR (P = 0.001). The association of HLAC1C1 and heterozygous GM23+/- was significantly associated with SVR (P = 0.001) and also subjects with HLA C1/C2 and heterozygous GM23+/- were likely to respond to treatment (P = 0.003) while subjects with HLA C1/C2 and GM23+ show tendency to resist to treatment (P = 0.0001). CONCLUSION: Our results didn't support a role for KM allotypes, GM23 allotype plays a role in the persistence of HCV infection in the presence or absence of KM1,3. Interaction between certain GM and HLA-C genotypes may favor adequate response to interferon based therapies.

Clinical outcomes of patients with insufficient sample from endometrial biopsy or curettage.

Endometrial biopsy and curettage are widely used uterine sampling procedures. Occasionally, the amount of tissue obtained is so minimal that diagnosis cannot be reached. In published studies, insufficient samples comprise 2% to 60% of endometrial samples and are influenced by multiple contributory factors. To date, specific quantitative criteria for an adequate endometrial sample have not been established in the pathology community. The decision to classify a sample as nondiagnostic is subject to great interobserver variability, especially where elderly patients are concerned. Meanwhile, whether or not to repeat the procedure is the dilemma for clinical management. Herein we studied the clinicopathologic features of 1120 endometrial samples designated as insufficient for diagnosis. Such samples were more commonly encountered in elderly patients than younger ones (14.6% vs. 5.8%). Our pathologists generally required one intact tissue fragment containing both glands and stroma for premenopausal patients and 5 to 10 strips of atrophic endometrial epithelium for postmenopausal patients. By the 12-mo follow-up, 38% of patients with nondiagnostic samples had second sampling procedures and 7% underwent hysterectomy. The second sample was adequate in 75% of patients, 10% of which showed malignant tumor. If any worrisome histologic findings were present in the initial nondiagnostic sample, a high percentage of these patients were found to have uterine malignancy on second procedures (43%). Aims of this study are to bring awareness to this commonly overlooked topic, to validate our diagnostic criteria, and to outline important clinical implications.

Diagnostic role of immunohistochemistry in the evaluation of breast pathology specimens.

CONTEXT: Immunohistochemistry plays a vital role in the evaluation of breast pathology specimens. OBJECTIVE: To discuss the role of myoepithelial cell markers in the evaluation of various breast lesions. Other markers, such as E-cadherin and those used to differentiate mammary carcinoma from metastatic tumors to the breast, and markers used in the differential diagnosis of Paget disease, are also discussed. DATA SOURCES: Data were obtained from review of the pertinent peer-reviewed literature. CONCLUSIONS: Myoepithelial cell markers vary in their sensitivity and specificity, and one should be aware of the potential pitfalls in interpretation. Using panels of 2 or more myoepithelial cell markers is always recommended, either singly or in cocktail forms. Although negative E-cadherin staining supports the diagnosis of lobular origin, positive staining does not rule it out. Immunohistochemistry can be helpful in differentiating Paget disease from its mimics. Although metastatic tumors to the breast are rare, a triple-negative immunophenotype and absence of an in situ component should be a "red flag" for such possibility, especially in patients with clinical history of an extramammary malignancy.

Fibroepithelial tumors of the breast: pathologic and immunohistochemical features and molecular mechanisms.

CONTEXT: The 2 main prototypes of fibroepithelial tumors of the breast include fibroadenoma and phyllodes tumor (PT). Although both tumors share some overlapping histologic features, there are significant differences in their clinical behavior and management. Phyllodes tumors have been further divided into clinically relevant subtypes, and there is more than one classification scheme for PT currently in use, suggesting a lack of consistency within different practices. Accurate differentiation between fibroadenoma and PT, as well as the grading of PT, may sometimes be challenging on preoperative core needle biopsy. Some immunohistochemical markers have been suggested to aid in the pathologic classification of these lesions. OBJECTIVE: To discuss the salient histopathologic features of fibroepithelial tumors and review the molecular pathways proposed for the initiation, progression, and metastasis of PTs. Also, to provide an update on immunohistochemical markers that may be useful in their differential diagnosis and outline the practice and experience at our institution from a pathologic perspective. DATA SOURCES: Sources included published articles from peer-reviewed journals in PubMed (US National Library of Medicine). CONCLUSIONS: Fibroepithelial tumor of the breast is a heterogenous group of lesions ranging from fibroadenoma at the benign end of the spectrum to malignant PT. There are overlapping histologic features among various subtypes, and transformation and progression to a more malignant phenotype may also occur. Given the significant clinical differences within various subtypes, accurate pathologic classification is important for appropriate management. Although some immunohistochemical markers may be useful in this differential diagnosis, histomorphology still remains the gold standard.

Basal-like breast cancer: update on clinicopathologic, immunohistochemical, and molecular features.

CONTEXT: Basal-like breast carcinoma (BLBC) is a distinct molecular subtype of breast carcinoma identified through gene expression profiling studies. OBJECTIVE: To provide the clinical background, the histologic profile, and the immunohistochemical profile of these tumors and discuss the current knowledge of their molecular signature and their implications on targeted molecular therapy. DATA SOURCES: Data were obtained from review of the pertinent peer-reviewed literature. CONCLUSIONS: Basal-like breast carcinomas are aggressive tumors with poor prognosis. Lack of targeted therapy makes their treatment a challenging task. Traditional chemotherapy is still associated with a high risk of relapse and death in a high percentage of patients. Platinum-based chemotherapy has been considered as a candidate for the treatment of BLBCs owing to their BRCA1 phenotype. Approximately 22% of patients treated with single-agent cisplatin show pathologic complete response, which is a comparable rate to that seen with nonplatinum agents. Antiangiogenic agents have been promising, but their currently demonstrated limited response is considered disappointing. Additionally, epidermal growth factor receptor was not shown to be a helpful target for BLBC. A recent study has shown that BLBC appears to be especially sensitive to MEK inhibitors, making it a promising therapeutic possibility. The list of new targets is still evolving and the "magic" therapeutic target is yet to be discovered.