Fatal case of luteinized thecoma with sclerosing peritonitis in a 40-year-old woman.

We describe the pathologic and clinical presentation of a very rare, fatal case of luteinized thecoma with sclerosing peritonitis in a 40-year-old woman, who had a history of total abdominal hysterectomy and a left salpingo-oophorectomy in 2003. The patient presented with abdominal pain, and radiologic examinations revealed a 10-cm heterogenous right pelvic mass with partial necrosis. The patient eventually underwent an exploratory laparotomy, which revealed an ovarian tumor with multiple implants in the peritoneal cavity. The ovarian lesion was made up of spindle cells among clusters of luteinized stromal cells that expanded to the ovarian cortex. Tumor cells were positive for vimentin, estrogen and progesterone receptors, and CCD68 (focally) and negative for CD34, α-smooth muscle actin, ß-catenin, and desmin by immunohistochemical studies. Luteinized cells were positive for α-inhibin and calretinin. Tumor cells exhibited low Ki-67 proliferation indices. The patient died because of the sclerosing peritonitis component of the disease.

Regulation of connective tissue growth factor gene expression and fibrosis in human heart failure.

BACKGROUND: Heart failure (HF) is associated with excessive extracellular matrix (ECM) deposition and abnormal ECM degradation leading to cardiac fibrosis. Connective tissue growth factor (CTGF) modulates ECM production during inflammatory tissue injury, but available data on CTGF gene expression in failing human heart and its response to mechanical unloading are limited. METHODS AND RESULTS: Left ventricle (LV) tissue from patients undergoing cardiac transplantation for ischemic (ICM; n = 20) and dilated (DCM; n = 20) cardiomyopathies and from nonfailing (NF; n = 20) donor hearts were examined. Paired samples (n = 15) from patients undergoing LV assist device (LVAD) implantation as "bridge to transplant" (34-1,145 days) also were analyzed. There was more interstitial fibrosis in both ICM and DCM compared with NF hearts. Hydroxyproline concentration was also significantly increased in DCM compared with NF samples. The expression of CTGF, transforming growth factor (TGF) ß1, collagen (COL) 1-α1, COL3-α1, matrix metalloproteinase (MMP) 2, and MMP9 mRNA in ICM and DCM were also significantly elevated compared with NF samples. Although TGF-ß1, CTGF, COL1-α1, and COL3-α1 mRNA levels were reduced by unloading, there was only a modest reduction in tissue fibrosis and no difference in protein-bound hydroxyproline concentration between pre- and post-LVAD tissue samples. The persistent fibrosis may be related to a concomitant reduction in MMP9 mRNA and protein levels following unloading. CONCLUSIONS: CTGF may be a key regulator of fibrosis during maladaptive remodeling and progression to HF. Although mechanical unloading normalizes most genotypic and functional abnormalities, its effect on ECM remodeling during HF is incomplete.

Prognostic utility of quantitative image analysis of microvascular density in prostate cancer.

The walls of angiogenic blood vessel capillaries are composed of two principal cell types, blood vessel endothelial cells (BEC) and pericytes (PC), whereas the walls of lymphatic capillaries are composed of lymphatic endothelial cells (LEC). In this investigation we describe a practical application of NIH ImageJ software for quantitative image analysis for pericytes and endothelial cells in prostate cancer. We used a tissue microarray that contained 49 tissue cores (normal prostate tissue or prostatic carcinomas with Gleason scores of 6 through 10). These prostate cancer samples represented AJCC prognostic stages II, III, and IV. Slides were immunostained with anti-PDGFR-ß antibody for identification of PC, and quantified as microvascular pericyte density (MVPD); they were also immunostained with anti-CD34 antibody for identification of LEC and BEC simultaneously, and quantified as microvascular endothelial density (MVED). CD31 and D2-40 immunostains were used to quantify BEC and lymphatic endothelial cells, respectively. Our results showed higher MVPD and MVED in prostate cancers with higher Gleason scores and higher stages, suggesting the prognostic utility of vascular image analysis in prostate pathology. This investigation demonstrates the feasibility, versatility, and ease of use of ImageJ software and pericyte-specific and endothelial-specific immunohistochemistry for quantitative image analysis in prostate pathology.

Thyroid transcription factor-1 and "basal marker"--expressing small cell carcinoma of the breast.

Small cell carcinoma of the breast is a very rare entity that is histologically indistinguishable from small cell carcinomas of other organs. The presence of an in situ component is the most important feature that indicates the primary nature of the breast tumor. Thyroid transcription factor-1 (TTF-1) is a marker specific to lung and thyroid but is also expressed in small cell carcinoma of pulmonary and extrapulmonary origin. TTF-1 expression in breast small cell carcinoma has been reported only rarely. This reported case is unique because of the characteristic morphological features and immunohistochemical profile. The invasive tumor demonstrated neuroendocrine differentiation morphologically and immunohistochemically, expressed by TTF-1, EGFR, and basal-type cytokeratins. An unequivocal in situ component was identified intimately admixed with the invasive carcinoma. To the authors' knowledge, this is the first report of breast small cell carcinoma showing the expression of "basal markers."

Analytic bias among certified methods for the measurement of hemoglobin A1c: a cause for concern?

We studied the magnitude, significance, and origin of an analytic bias that emerged between our point-of-care (POC) and our central laboratory (CL) methods for the measurement of hemoglobin A1c (HbA1c) and evaluated the analytic accuracy of 7 commonly used HbA1c methods relative to the National Glycohemoglobin Standardization Program (NGSP) reference method. The POC and CL methods were compared by split-sample analysis of clinical specimens and time series analyses of the HbA1c results reported for a 33-month period. The relative accuracies of 7 HbA1c methods were evaluated using College of American Pathologists proficiency survey results. Long-term drifts in the CL- and POC-analyzed test results caused the median intermethod bias [(POC result)-(CL result)] to increase from -0.4% to -0.9% HbA1c. Systematic biases, drifts in analytic performance over time, and intermethod variability were frequently observed among the 7 NGSP-certified HbA1c methods. Intermethod variability is a potential source of inaccuracy whenever HbA1c results are interpreted relative to universal, fixed, clinical decision thresholds.

Amiodarone lung toxicity in a cardiac transplant candidate initially diagnosed by fine-needle aspiration: cytologic, histologic, and electronmicroscopic findings.

A cardiac transplant candidate with ischemic cardiomyopathy developed bilateral small parenchymal opacities in lower lobes of the lung. A fine-needle aspiration (FNA) was performed that revealed changes characteristic of amiodarone toxicity. Subsequently performed lung biopsies and electron microscopic studies confirmed the initial FNA diagnosis. The patient has been successfully transplanted with marked improvement in his clinical findings. This is the first case of amiodarone lung toxicity where the diagnosis was initially suggested based on the FNA findings. We also describe the clinical, cytological, histological, and electron microscopic (EM) findings of amiodarone-related pulmonary toxicity and provide a review of the literature.

Constitutively active melatonin MT(1) receptors in male rat caudal arteries.

This study assessed the state of melatonin MT(1) receptor coupling in sections of male rat caudal arteries by [35S]GTPgammaS binding autoradiography. The melatonin MT(1) receptor inverse agonist 4-phenyl-2-propionamidotetraline (4P-PDOT) (0.1-1 microM) significantly decreased [35S]GTPgammaS binding compared to basal, strongly suggesting the presence of constitutively active receptors. Formation of constitutively active receptors during subjective day, when the levels of melatonin are low, may be a physiological mechanism by which the organism maintains vascular tone.

The functional role of Notch signaling in triple-negative breast cancer.

The term "triple-negative breast cancer" (TNBC) is a heterogeneous subtype of breast cancer. Unfortunately, due to the lack of expression of hormone receptors and human epidermal growth factor receptor-2, therefore the lack of US Food and Drug Administration-approved targeted therapies, TNBC has the worst prognosis of all subtypes of breast cancer. Notch signaling has emerged as a pro-oncogene in several human malignancies and has particularly been associated with the triple-negative subtype of breast cancer. This chapter explores the role of Notch signaling in triple negative and other subtypes of breast cancer, the relationship of Notch with other breast cancer biomarkers, prognostic indicators associated with Notch, and potential therapeutic strategies targeting Notch inhibition. Hopefully, better understanding of this signaling pathway in the future will lead to optimal molecular therapeutic treatments for TNBC patients, improving their quality of life and outcome.

Evaluation of biomarkers in multifocal/multicentric invasive breast carcinomas.

BACKGROUND: The purpose of this study was to evaluate whether breast carcinoma biomarkers vary among separate tumor foci of multifocal/multicentric (MF/MC) breast carcinomas and whether this variation correlates with morphological features and tumor grade. DESIGN: We reviewed the biomarker profiles of MF/MC invasive breast carcinomas diagnosed between January 2001 and June 2010 at our institution. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal receptor protein (HER2) results were classified as positive or negative. RESULTS: Out of the 51 patients included in the study, 6 cases had 2 tumor foci with different morphologies, 7 cases had 2 foci with similar morphology but different grades, and 38 cases had 2 tumor foci with similar morphologies and grades. Out of the 38 patients who had MF/MC tumors with the same morphology and grade, only 1 patient had a difference in ER and PR status between foci. Out of the 7 patients who had morphologically similar tumors with different grades, 4 had similar results in both tumor foci, 3 had different results for ER and PR, and another had differing results for HER2 between the foci. All 6 patients who had MF/MC foci with different morphologies exhibited similar ER, PR, and HER2 results between the foci. CONCLUSION: Regardless of the similarity in tumor morphology or grade, a small number of cases included foci that exhibited different tumor marker expression, which might affect the treatment strategy. Therefore, our results suggest that the evaluation of tumor markers in different foci should be considered in MF/MC tumors for accurate treatment strategies.

A practical application of quantitative vascular image analysis in breast pathology.

AIMS: Quantitative image analysis of histopathology slides is becoming an important technology in diagnostic pathology. To this end, it is essential to combine a robust image analysis software with the most commonly used immunohistochemical staining methods. In this investigation, we describe a practical application of NIH ImageJ software for quantitative vascular image analysis for diaminobenzene chromogen-based CD34 immunostain in breast cancer. CD34 immunostain is in a unique position to identify lymphangiogenesis and angiogenesis simultaneously in a given tumor tissue. This investigation aims at establishing a practical quantitative vascular image analysis solution for diagnostic pathologists by using ImageJ, and CD34 immunostain. METHODS AND RESULTS: Tissue microarray slides containing breast cancer tissue were immunostained for CD34 for simultaneous identification of lymphatic endothelial cells (LEC) and blood vessel endothelial cells (BEC). Digital images were analyzed using NIH ImageJ software. A CD34 score was quantified for each tissue core as a percentage (CD34-positive area/area of tissue core). The mean CD34 scores were 0.24%, 0.40%, 1.30%, 2.33%, 2.64%, and 3.44% for normal breast tissue, in stage IIA, IIB, IIIA, IIIB, and IIIC breast cancer tissue cores, respectively (p<0.0001). The mean CD34 scores were 0.70% and 2.21% for lymph node-negative and lymph node-positive breast cancer patients, respectively (p<0.0001). CONCLUSIONS: ImageJ software seems to be an attractive quantitative image analysis tool for diagnostic pathology for immunohistochemistry-based applications because of its capabilities, availability, and ease of use with most image formats. Our results show the feasibility, versatility, and ease of use of ImageJ and CD34 immunohistochemistry for vascular image analysis in breast pathology. Given the prospects of novel lymphatic and vascular endothelium-targeting therapeutics in breast oncology, the practical analysis of combined LEC and BEC density described in this report could enable diagnostic pathologists to apply quantitative vascular image analysis easily in their pathology practice and translational research.

Utility of p16, Ki-67, and HPV test in diagnosis of cervical intraepithelial neoplasia and atrophy in women older than 50 years with 3- to 7-year follow-up.

BACKGROUND: Differentiating cervical intraepithelial neoplasia (CIN) from atrophy in postmenopausal women based on morphology alone is challenging. p16 and Ki-67 help distinguish CIN2/3 from atrophy. The goal of this study is to further characterize the utility of p16, Ki-67, and human papillomavirus (HPV) tests in women older than 50 years, particularly in CIN1. DESIGN: The authors retrospectively identified cervical specimens from three, 1-year time periods. Included were cases from women older than 50 years with benign diagnoses, atrophy, and CIN. Slides were stained with p16 and Ki-67 and graded as positive or negative. Medical records were reviewed for cytology, HPV test, and histopathologic diagnoses from the time of biopsy to 2010. RESULTS: A total of 97 cervical samples were included. In all, 34 (74%) CIN1 cases were negative for p16 and Ki-67. Of CIN1 cases with positive HPV tests, only 1/10 (10%) had positive p16 staining versus 2/2 (100%) of CIN2/3 cases. Of 39 women with CIN1 who had follow-up data available, 4 (10%) had subsequent histologic progression to CIN2/3 and none developed invasive disease. CONCLUSIONS: In our study, the majority of cases (74%) diagnosed as CIN1 in women ≥ 50 years are negative for p16 and Ki-67 and do not progress to high-grade dysplasia during 3- to 7-year follow-up. A combination of morphology, p16, and Ki-67 on cervical specimens in women older than 50 years, and furthermore, use of these stains on Pap tests in combination with HPV testing may help distinguish CIN from atrophy and reduce unnecessary invasive follow-up testing.

The Effect of Cold Ischemia Time and/or Formalin Fixation on Estrogen Receptor, Progesterone Receptor, and Human Epidermal Growth Factor Receptor-2 Results in Breast Carcinoma.

Aims. To compare the results of estrogen and progesterone receptors (ER, PR), and human epidermal growth factor receptor-2 (HER2) expression status on biopsy and excision specimens and to evaluate the effect of cold ischemia time and/or formalin fixation on these biomarkers. Methods. Breast carcinomas that were diagnosed between 2007 and 2009 by core needle biopsy, and subsequently excised in our institution, were included in the study. Data regarding the tumor morphology, grade, and ER, PR, and HER2 status were retrospectively collected from the pathology reports. Results. Five out of 149 (3.4%) cases with ER-positive receptor status in the biopsy specimen became ER-negative in the subsequent excision specimen. Nine out of 126 (7.1%) cases with PR-positive receptor status in the biopsy specimen became PR-negative in the excision specimen. Receptor status change was predominantly seen in tumors with low ER and PR receptor expression. HER2 results were consistent between biopsy and excision specimens in all cases tested. Conclusions. Cold ischemia time and/or formalin fixation affect mainly ER and PR testing with low Allred scores and support the implementation of the ASCO/CAP guidelines. HER2 results, however, were not affected in our limited number of patients.

The prognostic value of lymph node cross-sectional cancer area in node-positive breast cancer: a comparison with N stage and lymph node ratio.

The number of positive axillary lymph nodes (LNs) is the only node-related factor for prognostic evaluation of breast cancer recognized by AJCC (TNM staging). However, N staging may not completely reflect LN tumor involvement due to the erroneous count of LNs in the presence of matted LNs and different tumor volume in LNs. Additionally, the positive/total LN ratio (LNR) has been shown to outperform N staging in survival prediction. In our study, to better quantify the tumor involvement of axillary LNs, we measured the cross-sectional cancer area (CSCA) of the positive LNs in 292 breast cancer patients diagnosed between 1998 and 2000 in our institution and compared its prognostic value to that of number of positive LNs (metLN)/N stage and LNR. Statistical analyses of these three LN-related factors were performed by Kaplan-Meier method and multivariate Cox's regression model. Patients were divided into three groups based on the different LN CSCA (<50, 50-500, and >500 mm(2)), or LNR (<0.1, 0.1-0.65, and >0.65), or N stage (N1-N3). Multivariate analysis demonstrated LNR was the most significant LN-related survival predictor with hazard ratio (HR) 25.0 (P = 0.001), compared to the metLN (HR 0.09, P = 0.052) and CSCA (HR 2.24, P = 0.323).

Wegener's disease presenting with occipital condyle syndrome.

Tumors or chronic inflammatory lesions of the occipital condyle may cause occipital pain associated with an ipsilateral hypoglossal nerve injury (occipital condyle syndrome). We describe a young woman with recurrent otitis media and occipital condyle syndrome associated with a limited form of Wegener's disease.

Notch-1 and Notch-4 biomarker expression in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) demonstrates lack of expression of hormone receptors and human epidermal growth factor receptor. However, there is no targeted therapy for TNBC. The authors analyzed 29 TNBC cases for Notch-1 and Notch-4 biomarker expression and subcellular location, Ki67 proliferation rate, and relevant clinical/survival data. Results demonstrated an unfavorable Ki67 rate in 90% of cases, Notch-1 expression in tumor and endothelial cells in 100% of cases, and Notch-4 expression in tumor cells in 73% of cases and endothelial cells in 100% of cases. Additionally, subcellular localization of Notch-1 and Notch-4 was predominantly nuclear and cytoplasmic. In conclusion, (a) the majority of TNBCs are high-grade infiltrating ductal carcinomas with high Ki67 proliferation rate and (b) both Notch-1 and Notch-4 receptors are overexpressed in tumor and vascular endothelial cells with subcellular localization different from that of hormone-positive breast cancer. Targeting Notch signaling with gamma secretase inhibitors should to be explored to further improve the survival rate of TNBC patients.

Pseudoangiomatous stromal hyperplasia (PASH) of the breast: a clinicopathological study of 79 cases.

BACKGROUND: Pseudoangiomatous stromal hyperplasia (PASH) of the breast is a benign lesion that can present as a palpable nodule or as an incidental finding in breast biopsies. DESIGN: The study comprised 79 cases diagnosed at Loyola University Medical Center from 2002 to 2009. The pathology slides were reviewed to document the distribution, type, and association with preneoplastic or neoplastic epithelial lesions. Z-test for independent proportions is used for analysis. RESULTS: A total of 76 patients were female and 3 were male. In all, 59.8% of patients presented with a breast mass and in 40.2% the lesion was an incidental finding. Classical PASH morphology was seen in 97.6% and proliferative PASH in 2.4%. Associated epithelial lesions were benign proliferative changes in 60.4%, atypical ductal and atypical lobular hyperplasia in 25.6% and infiltrating carcinoma in 11% of cases. CONCLUSIONS: Based on these results, extensive sampling of biopsy specimen with PASH and appropriate clinical and radiologic follow-up is recommended.

Basal-like subtype breast cancers in women older than 40 years of age.

Basal-like (BL) carcinoma, distinguished by the expression of keratins that are a characteristic of myoepithelial cells, is 1 of the 5 distinct subtypes of breast tumors identified by gene microarray technologies. BL cancers have been well described in women <40 years of age. However, little data exist about this carcinoma in older patients. Twenty-three BL breast cancer specimens from patients >40 years of age were evaluated. The study demonstrated that there is a subset of patients >40 years of age with breast cancers, manifesting features of BL carcinoma. There has been a significant increase in BL cancers among women >40 years of age having larger tumors and lymph node metastasis in comparison with younger women <40 years of age. This could be due to the tumor heterogeneity in BL cancers between the 2 age groups. BL cancer patients from all age groups require further investigation for BRCA-1, as well as gene microarray analysis to compare the gene expressions with those observed in the younger population.

Evaluation of morphologic features to identify "basal-like phenotype" on core needle biopsies of breast.

The basal-like phenotype (BLP) subtype of breast carcinoma has been identified as 1 of 5 tumor subtypes first revealed by microarray profiling. This phenotype tends to be more aggressive, is more often associated with BRCA1 mutations, and carries a poor prognosis. Few studies have morphologically characterized BLP on resected breast specimens (RS), and no studies have evaluated these diagnostic parameters in core needle biopsies (CNB) of breast. We identified a group of 35 RS that demonstrated BLP by morphology and/or immunophenotype based on the criteria used in the literature. Retrospectively, we reviewed the CNB of these RS for the following morphologic features: growth pattern, nuclear grade, mitotic rate, presence of ductal carcinoma in situ, necrosis, and lymphocytic response. Of these histologic features, solid growth pattern [88.6% (31/35)] with nuclear grade 3 [100% (35/35)], marked lymphocytic infiltrate [74.3% (26/35)], and absence or <5% of ductal carcinoma in situ [91.4% (32/35)] were seen most consistently in all the CNB. Geographic necrosis was seen in almost half of the cases [48.6% (17/35)]. Lymphovascular invasion and squamoid differentiation were limited to a small number of cases. On the basis of our results, we propose using certain morphologic features (solid growth pattern, high nuclear grade, presence of marked lymphocytic infiltrate, and geographic necrosis) in recognizing BLP on CNB. Triple negativity of estrogen receptor, progesterone receptor, and HER2/neu combined with positive BLP immunohistochemical markers such as the cytokeratins (CK): CK17, CK14, CK5/6, and epidermal growth factor receptor, help to further confirm the diagnosis.