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.

The effect of thrombocytopenia on dermal wound healing.

The immediate appearance of platelets in wounds and the ability of platelets to release growth factors suggest that platelets are an important trigger of the tissue repair process. To examine the effect of systemic thrombocytopenia on both the inflammatory and proliferative aspects of wound healing, adult mice were rendered thrombocytopenic by intraperitoneal administration of a rabbit antimouse platelet serum. Full-thickness excisional dermal wounds were prepared and analyzed for inflammatory cell content, growth factor production, reepithelialization, collagen synthesis, and angiogenesis at multiple time points after injury. Compared to control mice, thrombocytopenic mice exhibited significantly altered wound inflammation. Wounds of thrombocytopenic mice contained significantly more macrophages and T cells, yet exhibited neutrophil content similar to wounds from control mice. Surprisingly, thrombocytopenic mice exhibited no delay in the reparative aspects of wound healing. The rate of wound reepithelialization, collagen synthesis, and angiogenesis was nearly identical for thrombocytopenic and control mice. Analysis of vascular endothelial growth factor, fibroblast growth factor 2, transforming growth factor beta1, keratinocyte growth factor, and epidermal growth factor revealed no difference in the levels of these growth factors in the wounds of control and thrombocytopenic mice. Taken together, the results suggest that the presence of platelets may influence wound inflammation, but that platelets do not significantly affect the proliferative aspects of repair, including wound closure, angiogenesis, and collagen synthesis.

Neutrophil function in the healing wound: adding insult to injury?

Cells of the innate immune system, including neutrophils and macrophages, are a highly visible component of normal wound healing in adult mammals. The role of inflammatory cells in the healing wound has been widely investigated, and evidence for both positive and negative influences exists. Several recent investigations support the emerging paradigm that robust inflammation is detrimental to wound closure. This developing information suggests that the functional role of inflammatory cells in wound healing must be reevaluated.

Sp1 regulates cathepsin B transcription and invasiveness in murine B16 melanoma cells.

BACKGROUND: Increased expression of cathepsin B contributes to extracellular matrix degradation and invasion in cancer. Cathepsin B expression is under transcriptional control in murine melanomas and the major promoter contains potential binding sites for the Sp1 transcription factor. MATERIALS AND METHODS: Murine melanoma cells transfected with an Sp1 expression plasmid or its control were used in Matrigel invasion and cell motility assays in the presence or absence of the cathepsin B inhibitor, CA-074Me. RESULTS: Transfection of B16F1 cells with the Sp1 expression plasmid resulted in a 2.5- to 5.3 -fold increase in cathepsin B specific activity and a 4.8- to 5.5-fold increase in invasiveness over the control, but had no effect on the movement of cells across an uncoated membrane. CA-074Me treatment resulted in significantly reduced Matrigel invasion without affecting cell motility. CONCLUSION: Sp1 can regulate the capacity of B16F1 cells to degrade a reconstituted extracellular matrix in part by regulating cathepsin B expression.

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.

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).

Verucciform xanthoma of the penis not associated with human papillomavirus infection.

Verruciform xanthoma (VX) is a rare lesion with a predilection for oral mucosa. Only 16 cases of VX of the penis have been reported. Histologically, VX lesions in different locations are identical; however, the etiology is controversial. Previous studies have reported the presence of human papillomavirus (HPV) in VX of the skin. The purpose of this study was to determine whether HPV is a causative agent in this rare case of VX of the penis. Microscopically, the lesion demonstrated prominent verrucoid squamous hyperplasia with hyperkeratosis, parakeratosis, and acanthosis. Histiocytes, a hallmark of VX, were identified in the elongated dermal papillae. Nested polymerase chain reaction was performed on the DNA with the commonly used primer sets MY9/MY11 and GP5+/GP6+, which identify more than 40 HPV types. The results failed to identify HPV DNA in the sample, although HPV could be readily detected in genomic DNA extracted from paraffin-embedded condyloma acuminatum, a known HPV-associated lesion. Additionally, we tested a VX lesion of the palate for HPV DNA and obtained negative results. Our results indicate that VX can arise without HPV infection and suggest other possible origins may be involved.

Aminopeptidase P isozyme expression in human tissues and peripheral blood mononuclear cell fractions.

Aminopeptidase P (APP) isoforms specifically remove the N-terminal amino acid from peptides that have a proline residue in the second position. The mRNA levels of three different isoforms, each coded by a different gene, were determined in 16 human tissues and in peripheral blood mononuclear cell (PBMC) fractions by RT-PCR. The cytosolic isoform, APP1, and the cell surface membrane-bound isoform, APP2, are expressed in all of the human tissues and PBMC fractions examined. The very high expression of APP2 mRNA in kidney compared to other tissues was confirmed by enzyme activity measurements. Among the PBMC fractions, APP2 expression is highest in resting CD8(+) T cells, but decreases in these cells following their activation with phytohemagglutinin; in contrast, expression of APP2 increases in CD4(+) T cells upon activation. The third isoform, APP3, is a hypothetical protein identified by nucleotide sequencing. A detailed analysis of its amino acid sequence confirmed that the protein is an aminopeptidase P-like enzyme with greater similarity to Escherichia coli APP than to either APP1 or APP2. Two splice variants of APP3 exist, one of which is predicted to have a mitochondrial localization (APP3m) while the other is cytosolic (APP3c). Both forms are variably expressed in all of the human tissues and PBMC fractions examined.

Rat and mouse membrane aminopeptidase P: structure analysis and tissue distribution.

Membrane-bound aminopeptidase P (mAPP) is a highly specific exopeptidase that removes the N-terminal amino acid only from a peptide (three amino acids or longer) that has a prolyl residue in the second position. mAPP can inactivate bradykinin, a potent vasodilating and cardioprotective peptide hormone, by hydrolyzing the Arg(1)-Pro(2) bond. Studies on the rat have shown that the metabolism of bradykinin is an important physiological role of this enzyme. We report here the complete coding sequences for rat and mouse mAPP determined from mRNA isolated from lung tissue. Key structural features that determine post-translational processing and substrate recognition and catalysis were identified based on sequence homologies and the crystal structure of Escherichia coli aminopeptidase P complexed with Pro-Leu. The tissue-specific expression of mAPP was studied using the polymerase chain reaction. The mAPP gene is widely, but variably, expressed in adult tissues of the rat and mouse and in mouse embryos.