Russell R. Snyder

Infiltrating syringomatous adenoma of the nipple. A clinical and pathological study of 11 cases

The clinical and pathologic findings of 11 infiltrating syringomatous adenomas of the nipple (ISA) were studied. All neoplasms were composed of small ducts and solid strands of epithelial cells surrounded by desmoplastic stroma. Ten of the 11 invaded the smooth muscle of the nipple, four extended to underlying breast tissue, and one showed perineural invasion. All lesions had an infiltrative margin, but 10 were treated successfully by local excision, even though five (45%) recurred. None metastasized. ISA must be distinguished from nipple duct adenoma and tubular carcinoma. Its clinical significance lies primarily in its recognition as a distinctive benign neoplasm. In the past, a variety of terms have been used to describe this lesion, whether it occurred in the skin, nipple, or substance of the breast. “Infiltrating syringomatous adenoma” is the preferred term to avoid using “carcinoma” for lesions involving the breast.

Acute hemodynamic and respiratory effects of amniotic fluid embolism in the pregnant goat model

OBJECTIVE Our purpose was to determine the acute-phase central hemodynamic and respiratory effects of raw, filtered, filtered and boiled, and meconium-containing amniotic fluid. STUDY DESIGN Pregnant goats (Capra hircus) in the last one third of pregnancy were given freshly collected autologous amniotic fluid in a volume of 2.5 ml/kg of body weight. Observations were then made at 10, 30, 60, 120, and 180 minutes after amniotic fluid embolism. Pulmonary artery catheters and femoral artery lung water catheters were placed for specimen and data collection. RESULTS Marked pressor responses were observed in both the pulmonary and systemic circulations with all amniotic fluid infusions. The pressor response was similar with raw, filtered, and filtered and boiled amniotic fluid. The pressor response seen with amniotic fluid containing meconium was significantly greater than that seen with the other forms. No significant effects were observed on cardiac or respiratory function except in the meconium group, where transient left ventricular dysfunction was accompanied by an acute increase in extravascular lung water and dysoxia. CONCLUSIONS The Capra hircus model is appropriate for the further study of amniotic fluid embolism. The acute pressor effects are transient and involve both the systemic and pulmonary circulations. Left ventricular dysfunction and dysoxia were observed only with embolism of amniotic fluid containing meconium.

Structure-Function of the Tumor Suppressor BRCA1

BRCA1, a multi-domain protein, is mutated in a large percentage of hereditary breast and ovarian cancers. BRCA1 is most often mutated in three domains or regions: the N-terminal RING domain, exons 11-13, and the BRCT domain. The BRCA1 RING domain is responsible for the E3 ubiquitin ligase activity of BRCA1 and mediates interactions between BRCA1 and other proteins. BRCA1 ubiquitinates several proteins with various functions. The BRCA1 BRCT domain binds to phosphoproteins with specific sequences recognized by both BRCA1 and ATM/ATR kinases. Structural studies of the RING and BRCT domains have revealed the molecular basis by which cancer causing mutations impact the functions of BRCA1. While no structural data is available for the amino acids encoded by exons 11-13, multiple binding sites and functional domains exist in this region. Many mutations in exons 11-13 have deleterious effects on the function of these domains. In this mini-review, we examine the structure-function relationships of the BRCA1 protein and the relevance to cancer progression.

Trends in the National Distribution of Laparoscopic Hysterectomies From 2003 to 2010

STUDY OBJECTIVE The purpose of this analysis was to compare the trends in undergoing laparoscopic hysterectomy (versus abdominal or vaginal hysterectomy) based on patient age, race, median income and insurance type, from 2003 to 2010. DESIGN Retrospective study (Canadian Task Force classification II-3). SETTING National sample of hospital admissions after hysterectomy. PATIENTS Health Cost and Utilization Project-Nationwide Inpatient Sample database was used to review records of women who underwent hysterectomy for either menorrhagia or leiomyoma from 2003-2010. INTERVENTION The predicted probability of undergoing laparoscopic hysterectomy was determined for each year according to patient age, race, median income, and insurance type. The slopes of these values (i.e. the trend) was compared for each subgroup (i.e. black, white, Asian, etc.) in these categories. MAIN RESULTS A total of 530, 154 cases were included in this study. Total number of hysterectomies decreased by 39% from 60,364 to 36,835 from 2003 to 2010. The percent of hysterectomies that were laparoscopic increased from 11% in 2003 to 29% in 2010. All groups analyzed experienced an increase in predicted probability of undergoing a laparoscopic hysterectomy. Of all women undergoing hysterectomy, the probability of undergoing a laparoscopic hysterectomy remained highest for women who were less than 35 years old, white, with the highest median income, and with private insurance from 2003-2010. The slope was significantly greater for (1) white females versus all other races analyzed (p<0.01), (2) females in the highest income quartile versus females in the lowest income quartile (p<0.01) and (3) females with private insurance versus females with Medicaid (p<0.01) or Medicare (p<0.01). CONCLUSIONS There remains a gap in distribution of laparoscopic hysterectomies with regards to age, race, median income and insurance type that does not seem to be closing, despite the increased availability of laparoscopic hysterectomies.

Ovarian strumal carcinoid: immunohistochemical, ultrastructural, and clinicopathologic observations.

Summary A review of 13 ovarian strumal carcinoids in the files of the Armed Forces Institute of Pathology has established further evidence that these tumors have both endocrine and neuroendocrine differentiation. The two functional routes of differentiation occur even within individual tumor cells. Immunohistochemical reaction for thyroglobulin was positive in the strumal regions of all 12 cases tested. This positivity was also present in transitional zones where the thyroid follicles merged with nests of carcinoid cells. Electron microscopy performed in six cases showed cells with neuroendocrine granules in the thyroid follicles; these cells resemble the C-cells of the normal thyroid gland. An immunoperoxidase reaction for calcitonin, however, revealed no positivity in any of the cells corresponding to the neuroendocrine cells within the follicles or those in the carcinoid component. Variable positivity for serotonin was observed, however. It is proposed that cells within the struma that have morphologic similarities to the C-cells of the thyroid give rise to the carcinoid component. These cells appear capable of producing thyroglobulin as well as neuroendocrine granules.

Endometrioid Proliferative and Low Malignant Potential Tumors of the Ovary: A Clinicopathologic Study of 46 Cases

We evaluated 41 endometrioid neoplasms with features intermediate between a benign endometrioid tumor and endometrioid carcinoma. Although these tumors showed various degrees of epithelial proliferation, they lacked the destructive stromal invasion of carcinoma. Intermediate endometrioid tumors were subdivided into proliferative endometrioid tumors (PET), endometrioid tumors of low malignant potential (ETLMP), and ETLMP with microscopic areas of invasion. PET were adenofibromas with solid aggregates of epithelial proliferation not exceeding 5 mm in any dimension, whereas ETLMP either had noninvasive cytologically malignant epithelium or aggregates of atypical epithelium measuring at least 5 mm in any dimension uninterrupted by fibromatous stroma. Of the seven PET, five were purely adenofibromatous, while two were mixtures of adenofibromatous and papillary components. Of the 31 ETLMP, 12 were adenofibromatous and 19 were either purely papillary or had mixtures of papillary and adenofibromatous components. An additional three ETLMP had one or more areas of microscopic invasion of the stroma in the form of an irregular or cribriform infiltration by atypical glands, often with squamous differentiation. These three neoplasms were designated “ETLMP with microinvasive carcinoma.” The only neoplasm with extraovarian implantation at presentation, however, was an ETLMP with mixed adenofibromatous and papillary features, without microinvasion. None of the other patients with ETLMP had a metastasis or developed one within a follow-up period of between 0.8 and 11.2 years. Because they are very low-grade neoplasms, ETLMP should be separated from endometrioid carcinoma and not confused with PET, because PET have no malignant potential.

The BRCA1 tumor suppressor binds to inositol 1,4,5-trisphosphate receptors to stimulate apoptotic calcium release

Background: The non-nuclear BRCA1 tumor suppressor can stimulate cell death, but the mechanisms are unknown. Results: BRCA1 binds to the inositol 1,4,5-trisphophate receptor (IP3R) calcium channel at the endoplasmic reticulum to stimulate apoptotic calcium release. Conclusion: BRCA1 tumor suppressor activity includes direct stimulation of apoptotic cell death via increased IP3R activity. Significance: We identify a novel role for the tumor suppressor BRCA1. The inositol 1,4,5-trisphosphate receptor (IP3R) is a ubiquitously expressed endoplasmic reticulum (ER)-resident calcium channel. Calcium release mediated by IP3Rs influences many signaling pathways, including those regulating apoptosis. IP3R activity is regulated by protein-protein interactions, including binding to proto-oncogenes and tumor suppressors to regulate cell death. Here we show that the IP3R binds to the tumor suppressor BRCA1. BRCA1 binding directly sensitizes the IP3R to its ligand, IP3. BRCA1 is recruited to the ER during apoptosis in an IP3R-dependent manner, and, in addition, a pool of BRCA1 protein is constitutively associated with the ER under non-apoptotic conditions. This is likely mediated by a novel lipid binding activity of the first BRCA1 C terminus domain of BRCA1. These findings provide a mechanistic explanation by which BRCA1 can act as a proapoptotic protein.

Detection of benign Endometrial masses by endometrial stripe measurement in premenopausal women

OBJECTIVE: Our objective was to estimate whether a transvaginal endometrial stripe of less than 5 mm in premenopausal women would exclude endometrial polyps and intracavitary leiomyomata, thereby eliminating the need for sonohysterography. METHODS: Data from 206 consecutive sonohysterograms performed in premenopausal women with abnormal uterine bleeding between August 1998 and October 2001 were collected retrospectively. Endometrial stripe measurements were obtained in the sagittal plane before sonohysterography. Baseline endometrial stripe images were reviewed by one of the authors, who was blinded to sonohysterography and pathology results, to evaluate for gross endometrial abnormalities on transvaginal ultrasonography. RESULTS: Endometrial stripe measurements were obtained before sonohysterography in 200 of the 206 consecutive exams in premenopausal subjects. Of the 80 subjects with an endometrial stripe measurement less than 5 mm, 11 had endometrial polyps and 5 had submucosal fibroids on sonohysterography. With an endometrial stripe thickness of less than 5 mm, the sensitivity was 74% (95% confidence interval 62–84), the specificity was 46% (95% confidence interval 38–54), the positive predictive value was 37%, and the negative predictive value was 80%. The detection of pathology was not improved by excluding cases with an abnormal-appearing endometrial stripe on the baseline transvaginal images. The use of other endometrial stripe cutoff values did not improve the diagnostic accuracy. CONCLUSION: Using an endometrial stripe cutoff of 5 mm in premenopausal women would miss significant intracavitary pathology. The sonographic evaluation of abnormal uterine bleeding in premenopausal women should include sonohysterography or equivalently accurate testing regardless of endometrial stripe thickness. LEVEL OF EVIDENCE: II-3

Evaluation of the impact of intraobserver variability on endometrial dating and the diagnosis of luteal phase defects.

OBJECTIVE To determine the magnitude of intraobserver variation in dating endometrial biopsies and its impact on clinical management. DESIGN Blinded histopathologic interpretation of endometrial biopsy specimens 1 year apart by five pathologists. SETTING Large military tertiary care center. PATIENTS Endometrial biopsy specimens from 51 patients undergoing evaluation for potential luteal phase defects. INTERVENTIONS None. MAIN OUTCOME MEASURES Calculation of the magnitude of the individual and overall intraobserver variation in endometrial dating for the five pathologists and estimation of its potential impact on clinical management. RESULTS The intraobserver variation was 0.69 +/- 0.05 days (means +/- SE). There was no significant difference in the magnitude of the variation for 1-day or 2-day dating ranges. The theoretical probability of altering clinical management by having the same pathologist redate a given specimen ranged from 15% to 28%. CONCLUSION Histologic dating of endometrial biopsies is subject to a small but highly clinically significant intraobserver variability that may have a major impact on clinical management.

Simvastatin Potently Induces Calcium-dependent Apoptosis of Human Leiomyoma Cells

Background: Statins have broad-reaching effects beyond lowering plasma lipids, including antitumor properties. Results: Simvastatin inhibits proliferation and induces calcium-dependent apoptosis of human uterine leiomyoma cells. Conclusion: We report a novel calcium-mediated pathway associated with antitumor properties of simvastatin. Significance: Simvastatin may have antitumor properties significant for the treatment of human uterine leiomyomas. Statins are drugs commonly used for the treatment of high plasma cholesterol levels. Beyond these well known lipid-lowering properties, they possess broad-reaching effects in vivo, including antitumor effects. Statins inhibit the growth of multiple tumors. However, the mechanisms remain incompletely understood. Here we show that simvastatin inhibits the proliferation of human leiomyoma cells. This was associated with decreased mitogen-activated protein kinase signaling and multiple changes in cell cycle progression. Simvastatin potently stimulated leiomyoma cell apoptosis in a manner mechanistically dependent upon apoptotic calcium release from voltage-gated calcium channels. Therefore, simvastatin possesses antitumor effects that are dependent upon the apoptotic calcium release machinery.