High-risk HPV testing improves accuracy in detection of CIN2+ lesions in ASC-H postmenopausal women? An academic hospital experiences.

Reflex human papilloma virus (HPV) testing with "atypical squamous cells, cannot exclude high-grade squamous lesion (ASC-H)" cytologic diagnosis is not recommended by American Society for Colposcopy and Cervical Pathology guidelines. Studies have shown human papillomavirus (HPV)-negative ASC-H patients of increased age are low risk for cervical intraepithelial neoplasia 2 or worse (CIN2+) lesions on colposcopic follow-up. We retrospectively assessed the efficacy of reflex HPV testing in postmenopausal women with ASC-H in the Los Angeles County hospitals and clinics in a 5-year period. Of a total 85 clinically postmenopausal women with ASC-H, 31 (36.5%) women were found to have CIN2+ lesions on follow-up biopsy and five of them were HPV-negative. Of the women with CIN2+ lesions and positive HPV, 13 (41.9%) were high-risk HPV (hrHPV) 16/18/45 positive and 13 (41.9%) were hrHPV-other subtype positive. Women with positive HPV had an over 3-fold increased risk of developing CIN2+ lesions (P = 0.008). Relative risk of hrHPV16/18/45 was 1.79-fold higher than that of hrHPV-other subtype. The positive predictive value and negative predictive value of hrHPV were 49.1% and 84.4%, respectively. CIN2+ detection rate in Hispanic women with positive hrHPV was higher than in non-Hispanic women (53.8% versus 35.7%). Overall, postmenopausal women with ASC-H cytology result and negative hrHPV were less likely to develop CIN2+ lesions, whereas about half of ASC-H postmenopausal women develop CIN2+ lesions if hrHPV positive, especially if hrHPV 16/18/45 positive. Therefore, triaging ASC-H postmenopausal women with cotesting or, ideally, hrHPV genotyping should be considered as optimal clinical practice to avoid overtreatment.

Performance of breast fine needle aspiration as an initial diagnostic tool: A large academic hospital experience.

BACKGROUND: The clinical performance of the Yokohama reporting system for breast cytology remains uncertain. METHODS: In this study, we retrospectively evaluated 318 breast fine needle aspirations (FNABs) from Los Angeles County Hospital over a five-year period, analysing data for breast cytology, histology, and radiology. RESULTS: Among 318 breast FNAB cases, 78.3% (249/318) were benign and 5.3% (17/318) malignant. Of 83 cases with follow-up histology, 14.5% (12/83) were insufficient, 66.3% (55/83) were benign, and 16.9% (17/83) were malignant. Of 55 benign cases, 61.8% (34/55) were fibroadenoma and 9 (9/55, 16.4%) were fibrocystic changes. Two cases were diagnosed as "atypical" but confirmed "benign" on core needle biopsy (CNB). No "suspicious" cases were found. Seventeen malignant cases were confirmed by CNB, including 70.6% (12/17) invasive ductal carcinoma, 11.8% (2/17) invasive lobular carcinoma, and one malignant phyllodes tumour. Receptor studies on cell blocks of three malignant cases showed concordant results with CNB results. In addition, 82.2% (148/180) of lesions with Breast Imaging-Reporting and Data System (BI-RADS) scores of 2 or 3 were benign and 92.3% (12/13) BI-RADS score 5 lesions were malignant on FNAB. Finally, 90% (67/74) of BI-RADS 4a lesions were benign, and 97% (36/37) of fibroadenomas were BI-RADS score 4a. CONCLUSION: This, by far the largest U.S. breast cytology study, showed 93.3% sensitivity, 100% specificity, 100% positive predictive value, and 98.2% negative predictive value for breast FNAB. Women with breast lesions of BI-RADS score 3 or less have a low risk of malignancy; FNAB would contribute to the reduction of excisional biopsies. FNAB can be considered as an initial diagnostic tool for BI-RADS 4 mass/lesions and satellite lesions, as well as for triaging patients.

Borderline Brenner Tumor of the Ovary Coexisting With an Ovarian Mucinous Cystadenoma With Focal Atypical Epithelial Proliferation: A Rare Case With Review of the Literature.

Ovarian Brenner tumors, accounting for ∼5% of overall ovarian epithelial neoplasm, are often reported in association with mucinous neoplasm. Histogenetically, the two tumors are thought to arise from similar precursors. To date, fewer than 60 borderline Brenner tumors alone have been reported, and the concomitant presence of atypical proliferative components in Brenner and mucinous tumors is even rarer. Therefore, the clinicopathological characteristics and prognosis of patients with the borderline Brenner tumors alone or coexisting with mucinous neoplasm are extremely limited. Herein, we report a unique case of a 53-year-old woman with a unilateral ovarian borderline Brenner tumor associated with focal atypical mucinous epithelial proliferation and her clinical presentations. The clinicopathological features of the tumor are documented and the literature review along with the clinical molecular advances are summarized in this study.

High-Grade Endometrioid Carcinoma of the Endometrium With a GATA-3-Positive/PAX8-Negative Immunophenotype Metastatic to the Breast: A Potential Diagnostic Pitfall.

This report describes clinicopathologic findings from the case of a patient with a breast mass that was ultimately diagnosed as a metastatic high-grade endometrioid carcinoma of endometrial origin. The breast lesion as well as the solid areas of the endometrial lesion displayed a similar immunoprofile: GATA3-positive; synaptophysin positive; negative for mammaglobin, gross cystic disease fluid protein-15, chromogranin, estrogen receptor, progesterone receptor, and HER2/neu; and intact expression of the DNA mismatch repair proteins MLH1, MSH2, MSH6, and PMS2. The breast lesion was negative for PAX-8, whereas the solid areas of the endometrial lesion showed focal weak positivity. A review of the literature on GATA-3 expression in endometrial carcinomas found a reported frequency of expression that ranged from 0% to 13% of cases, typically in a patchy, focal, and generally restricted pattern. However, GATA-3 may be diffusely expressed in high-grade endometrial carcinomas. Since the potential for PAX-8 expression to be lost in high-grade endometrioid carcinomas is well known, a GATA-3-positive/PAX8-negative immunoprofile may be encountered in high-grade endometrioid carcinomas of the endometrium, and this composite immunoprofile is a potential diagnostic pitfall when such a lesion is being evaluated in a breast metastasis.

Clostridium difficile toxins A and B decrease intestinal SLC26A3 protein expression.

Clostridium difficile infection (CDI) is the primary cause of nosocomial diarrhea in the United States. Although C. difficile toxins A and B are the primary mediators of CDI, the overall pathophysiology underlying C. difficile-associated diarrhea remains poorly understood. Studies have shown that a decrease in both NHE3 (Na+/H+ exchanger) and DRA (downregulated in adenoma, Cl-/[Formula: see text] exchanger), resulting in decreased electrolyte absorption, is implicated in infectious and inflammatory diarrhea. Furthermore, studies have shown that NHE3 is depleted at the apical surface of intestinal epithelial cells and downregulated in patients with CDI, but the role of DRA in CDI remains unknown. In the current studies, we examined the effects of C. difficile toxins TcdA and TcdB on DRA protein and mRNA levels in intestinal epithelial cells (IECs). Our data demonstrated that DRA protein levels were significantly reduced in response to TcdA and TcdB in IECs in culture. This effect was also specific to DRA, as NHE3 and PAT-1 (putative anion transporter 1) protein levels were unaffected by TcdA and TcdB. Additionally, purified TcdA and TcdA + TcdB, but not TcdB, resulted in a decrease in colonic DRA protein levels in a toxigenic mouse model of CDI. Finally, patients with recurrent CDI also exhibited significantly reduced expression of colonic DRA protein. Together, these findings indicate that C. difficile toxins markedly downregulate intestinal expression of DRA which may contribute to the diarrheal phenotype of CDI. NEW & NOTEWORTHY Our studies demonstrate, for the first time, that C. difficile toxins reduce DRA protein, but not mRNA, levels in intestinal epithelial cells. These findings suggest that a downregulation of DRA may be a critical factor in C. difficile infection-associated diarrhea.

Sebaceous carcinoma of the breast in a patient with a pathogenic BRCA2 (886delGT) mutation - focus on histopathologic and immunohistochemical features.

Sebaceous carcinoma of the breast (SCB) is a rare variant of ductal carcinoma arising within the mammary gland and containing at least 50% of malignant cells with sebaceous differentiation. Only 11 cases that adjust to the criteria delineated in the WHO classification have been published in the English literature, to the best of our knowledge. Here, we present the first SCB arising in the context of a deleterious BRCA2 mutation, focusing on the histopathologic and immunohistochemical features of this exceedingly rare tumor.

Primary Carcinosarcoma of the Pancreas With CD10-Positive Sarcoma Component.

Carcinosarcomas of the pancreas are rare entities with a dismal prognosis. We report a rare case of pancreatic carcinosarcoma in a 49-year-old African American female who underwent a total abdominal hysterectomy with right salpingo-oophorectomy and exploration of the pancreatic mass. The surgery revealed a sclerotic mass in the body and tail of the pancreas that was surgically unresectable, and a pancreatic biopsy confirmed the pathology of pancreatic carcinosarcoma. Histologically, the lesion showed a high-grade spindle cell sarcoma and adjacent moderately differentiated adenocarcinoma. On immunohistochemical examination, the carcinomatous component was positive for epithelial markers, and the sarcomatous component was focally positive for SMA and desmin. In addition, the sarcomatous component showed diffuse immunoreactivity for CD10 with a surrounding myofibroblastic proliferation. Reports have associated expression of CD10 in pancreatic stellate cells with increased tumor aggressiveness. In this article, we report a case of pancreatic carcinosarcoma that shows sarcomatous CD10 immunoexpression with higher Ki67 labeling in the sarcoma than the carcinoma raising the question if the sarcomatous component could be potentiating the aggressiveness of the carcinomatous component.

Opioid and melanocortin receptors: do they have overlapping pharmacophores?

We have identified compound 1 as a novel ligand for opioid and melanocortin (MC) receptors, which is derived from the overlapping of a well known structure for the delta opioid receptor, 2,6-dimethyltyrosine (Dmt)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), and a small molecule for the MC receptor, Tic-DPhe(p-Cl)-piperidin-4-yl-N-phenyl-propionamide. Ligand 1 showed that there is an overlapping pharmacophore between opioid and MC receptors through the Tic residue. The ligand displayed high biological activities at the delta opioid receptor (Ki = 0.38 nM in binding assay, EC(50) = 0.48 nM in GTP-gamma-S binding assay, IC(50) = 74 nM in MVD) as an agonist instead of an antagonist and showed selective binding affinity (IC(50) = 2.3 muM) at the MC-3 receptor rather than at the MC-5 receptor. A study of the structure-activity relationships demonstrated that the residues in positions 2, 3, and the C-terminus act as a pharmacophore for the MC receptors, and the residues in positions 1 and 2 act as a pharmacophore for the opioid receptors. Thus, this structural construct can be used to prepare chimeric structures with adjacent or overlapping pharmacophores for opioid and MC receptors.