Comparative transcriptome analysis of the human endocervix and ectocervix during the proliferative and secretory phases of the menstrual cycle.

Despite extensive studies suggesting increased susceptibility to HIV during the secretory phase of the menstrual cycle, the molecular mechanisms involved remain unclear. Our goal was to analyze transcriptomes of the endocervix and ectocervix during the proliferative and secretory phases using RNA sequencing to explore potential molecular signatures of susceptibility to HIV. We identified 202 differentially expressed genes (DEGs) between the proliferative and secretory phases of the cycle in the endocervix (adjusted p < 0.05). The biofunctions and pathways analysis of DEGs revealed that cellular assembly and epithelial barrier function in the proliferative phase and inflammatory response/cellular movement in the secretory phase were among the top biofunctions and pathways. The gene set enrichment analysis of ranked DEGs (score = log fold change/p value) in the endocervix and ectocervix revealed that (i) unstimulated/not activated immune cells gene sets positively correlated with the proliferative phase and negatively correlated with the secretory phase in both tissues, (ii) IFNγ and IFNα response gene sets positively correlated with the proliferative phase in the ectocervix, (iii) HIV restrictive Wnt/ß-catenin signaling pathway negatively correlated with the secretory phase in the endocervix. Our data show menstrual cycle phase-associated changes in both endocervix and ectocervix, which may modulate susceptibility to HIV.

Restoration of distorted colour microscopic images from transverse chromatic aberration of imperfect lenses.

An algorithm is presented for restoration of colour microscopic images with distortions from imperfect microscope lenses having transverse chromatic aberrations, resulting in a magnification that slightly varies with wavelengths or colours. The differential of each colour component image is computed as the difference between the component image and its slightly magnified version. The absolute values in the differential component images are generally higher at the edges where greater discontinuities occur. The two cross-correlation functions of the absolute differentials between red and green colours and between red and blue colours are then computed. The maximum in the two cross-correlation functions were sought, respectively, and the cross-correlation delays were then calculated. The two cross-correlation delays were used to determine dispersions and to realign the three colour components. Results of real microscopic images are provided. The restored image and the original are compared both visually and quantitatively in terms of the estimated entropies measured for the degree of concentrations using vector distributions.

Malignant pericardial effusion with cardiac tamponade in a patient with metastatic vaginal adenocarcinoma.

Malignant pericardial effusion with cardiac tamponade is a rare manifestation of metastatic gynecological cancer. A 35-year-old female was diagnosed with clear cell adenocarcinoma of the vagina. Four years after partial vaginectomy, she developed regional recurrence and was treated with surgical excision followed by platinum-based chemotherapy and radiation therapy. Six years later, the patient was diagnosed with lung metastases and received a combination adriamycin and platinum-based chemotherapy. Shortly after completing treatment, she presented with weakness and was found to be hypotensive on physical exam. Computed tomography scan confirmed a pericardial effusion with evidence of bilateral heart failure. She underwent an emergent pericardiocentesis and eventual pericardial window procedure. Metastatic adenocarcinoma of the vagina can present with malignant pericardial effusion with cardiac tamponade. Therefore, gynecologists and gynecological oncologists need to be familiar with the diagnosis and management of this disease process.

Obstacles to the early detection of endocervical adenocarcinoma.

We observed that the ratio of in situ to invasive carcinomas of the cervix is significantly greater for squamous than for glandular lesions. We wondered whether Pap smears were less effective for the identification of in situ glandular lesions. The purpose of this study was to determine if the location, extent of disease, and growth patterns of endocervical adenocarcinomas influence the ability to detect malignant cells by Pap smears. Medical records, doctor's office records, and all pathology materials (reports and slides) including Pap smears, biopsies, LEEP/cone biopsies, and hysterectomy specimens from 53 consecutive patients diagnosed with endocervical adenocarcinomas were examined at New York University Medical Center (a total of 654 pathology slides and 51 Pap smears were reviewed). Findings were correlated for each patient using gross descriptions and histopathology and stratified by location/extent of disease and growth pattern (exophytic or endophytic or both). Ten patients had in situ disease, seven (70%) of which involved the transformation zone (TZ); all seven of these were identified by Pap smears. In contrast, of the other three cases that did not involve the TZ but were confined to the endocervix, only one was identified by Pap smear. Forty-three patients had invasive disease. Twenty involved the TZ, and 23 involved the endocervix but spared the TZ. Of the 20 tumors involving the TZ, 11 (55%) were identified by Pap smears, whereas of the 23 sparing the TZ, 11 (47.8%) were diagnosed by Pap smear. Among the 23 patients with invasive disease that spared the TZ, 6 (26%) had a documented history of negative Pap smears at New York University within 3 years of diagnosis. Conversely only 1 of the 20 patients with TZ involvement had a history of negative Pap smears, and 3 patients in this group denied having had Pap smears for several years. Including all 53 patients, a significantly higher proportion were not detectable by Pap smear if the TZ was spared (54% versus 25%, p = 0.036). Of the 23 invasive cancers that spared the TZ, 6 (14%) had verified negative Pap smears. These lesions did not shed malignant cells onto Pap smears. Noteworthy was the finding that two of these six lesions extended from the endocervix upward, through the stroma, and into the endomyometrium of the lower uterine segment. Four extended downward into the exocervix through the stroma, sparing the surface mucosa; one reached the upper vagina. All six displayed an endophytic growth pattern.

The clinical importance of atypical glandular cells of undetermined significance on the cytologic smear.

The objective of the study was to assess the prevalence of underlying cervical and endometrial lesions among patients with atypical glandular cells of undetermined significance (AGCUS) on the cytologic smear. Eighty-six patients with AGCUS, without evidence of squamous intraepithelial lesions, underwent coloposcopy and endocervical curettage (ECC) within 6 months of the initial finding. Endometrial samplings were performed in 25 patients. Coloposcopy, endocervical curettage, and endometrial biopsy results were reviewed. A significant lesion was defined as cervical intraepithelial neoplasia and/or any structural or histologic abnormality of the cervix or uterus (i.e., polyp). Statistical analyses were performed using the t test, chi-square, and Fisher's Exact tests comparing patients with underlying lesions to those without. A significant lesion(s) was identified in 21 (24.4%) patients, with 8 (9.3%) of the lesions being high-grade cervical neoplasias. An additional 14 (16.3%) patients, with negative initial work-ups, had underlying lesions or major cytologic abnormalities diagnosed on subsequent follow-up. All of the endometrial findings were benign. None of the following were statistically significant predictors of underlying pathology: age, gravidy, parity, medications, medical history, tobacco use, history of sexually transmitted diseases including human immunodeficiency virus, previous abnormal cytologic smear, concurrent diagnosis of atypical squamous cells of undetermined significance, or evidence of human papillomavirus. AGCUS is often associated with clinically important underlying lesions. Patients should therefore undergo colposcopy and ECC. Endometrial sampling and possible cervical conization should be performed when coloposcopic evaluation is nondiagnostic.

Morphometric and electron microscopic analyses of the effect of gonadotropin-releasing hormone agonist treatment on arteriole size in uterine leiomyomas.

BACKGROUND: Few studies have been performed on the vascular changes in leiomyomas from patients treated with gonadotropin-releasing hormone agonists (GnRHAs). OBJECTIVE: To measure luminal diameter and wall thickness of arterioles in uterine leiomyomas using a quantitative stereologic method of analysis. DESIGN: Thirty leiomyomas from 3 study groups were used: (1) patients treated with GnRHAs (10 patient samples), (2) age-matched controls (10 patient samples), and (3) postmenopausal women (10 patient samples). Measurements of arteriolar luminal diameter and wall thickness were made using a video-based, computerized system attached to the microscope, for which a morphometric ad hoc program was written. Electron micrographs were made of random arterioles from the first 2 groups (GnRHA-treated patients and age-matched controls). SETTING: Department of Pathology, Mount Sinai School of Medicine, New York, NY. PATIENTS: A total of 30 patient samples were studied, with 3 groups comprising 10 samples each, including patients treated with GnRHAs, age-matched control patients, and postmenopausal women. RESULTS: Arterioles in myomas from patients treated with GnRHAs had slightly larger luminal diameters and significantly thicker walls than age-matched controls and resembled arterioles from postmenopausal women. The thickening was due to smooth muscle cell hyperplasia in the muscularis media. CONCLUSIONS: Treatment with GnRHAs causes a thickening of the walls of intramyomatous arterioles, which resemble those of postmenopausal women. This thickening may play a role in the decreased flow of blood reported in GnRHA treatment.

Founder BRCA 1 and 2 mutations among a consecutive series of Ashkenazi Jewish ovarian cancer patients.

OBJECTIVE: The purpose of this study was to describe the incidence of the three Ashkenazi Jewish founder genetic BRCA 1 and 2 mutations among an unselected, consecutive group of Ashkenazi Jewish ovarian cancer patients. MATERIALS AND METHODS: From 7/30/96 to 4/12/99, 92 Ashkenazi Jewish patients with histologically confirmed epithelial ovarian cancer had surgery. All of these patients had DNA extracted from 5-microm sections of their paraffin-embedded surgical specimen tissue blocks using the Qiagen QIAamp tissue extraction kit. A multiplex (triplex) polymerase chain reaction was performed to amplify fragments for the 185delAG, 5382insC, and 6174delT mutations. The products were hybridized with normal and mutant probes for each of the three mutations. All clinical data were collected retrospectively and statistical significance was evaluated using the chi(2) test or a two-tailed Fisher's exact test, depending on the sample size. RESULTS: There were 23 patients positive for one of the three founder BRCA mutations. Fourteen patients were positive for the 185delAG mutation, 2 patients were positive for the 5382insC mutation, and 7 patients were positive for the 6174 delT mutation (61, 9, and 30%, respectively). This represented a 25% incidence (95% CI: 16-34%) of one of the three founder BRCA mutations among our 92 Ashkenazi Jewish ovarian cancer patients. None of the patients was positive for more than one mutation. There was no statistically significant difference in parity, histology, grade, or stage between the BRCA founder mutation positive and negative patients. The difference between the percentage of mutation carriers among patients with one affected first-degree relative (13/22 or 59%) compared to those without at least one affected first-degree relative (10/70 or 14%) was highly significant (P = 0.001). CONCLUSIONS: Ashkenazi Jewish ovarian cancer patients represent a group with a high likelihood of being carriers of BRCA 1 and 2 genetic mutations, regardless of family history. As a result, all ovarian cancer patients who are of Ashkenazi Jewish descent should be counseled regarding BRCA 1 and 2 genetic screening, as well as the potential implications of these results for the patient as well as her relatives in terms of prognosis, screening, chemoprevention, and consideration of prophylactic surgical procedures.

Endometrial histopathology in 700 patients treated with tamoxifen for breast cancer.

OBJECTIVE: The aim of this study was the evaluation of endometrial histopathologic findings from 700 patients treated with tamoxifen (Tx) for breast cancer from two medical centers (United States and France). METHODS: A retrospective review of data including histologic slides from 134 hysterectomies and 566 endometrial biopsies from Tx-treated patients who presented with abnormal vaginal bleeding and/or abnormal sonograms was performed. Analysis of histologic characteristics included inactive/atrophic and functional endometria, endometrial polyps, hyperplasia and metaplasia, and endometrial cancer. Duration of Tx therapy was recorded when available, and its correlation with endometrial pathology was assessed. RESULTS: The only statistically significant difference between the data from the United States and France was the number of hysterectomies, which was almost double in France (27% vs 13.7%). Nonpathologic endometria made up 61.14% (inactive/atrophic 46%, functional 15.14%). Pathologic changes were found in 39.86% cases, of which polyps were 23.14%, glandular hyperplasia 8%, and metaplasia 3%; endometrial cancer made up 4.71% (33 cases). Nine cancers were well-differentiated endometrioid adenocarcinomas, and 24 were moderately or poorly differentiated, of which 13 had nonendometrioid components (serous, clear cell, MMMT). Fifteen cancers were found in endometrial polyps; 12 were invasive to the myometrium and 4 to blood vessels. The weight of the uteri exceeded 300 g in 15 cases, with 4 exceeding 900 g. The average age of all patients was 60.91 years and of the cancer patients alone it was 69.26 years. The shortest average duration of Tx therapy (2.5 years) was found in patients with inactive/atrophic endometria and the longest (6.8 years) in patients with endometrial cancer. Patients with endometrial polyps and cancer presented more often with abnormal vaginal bleeding than those with inactive/atrophic endometrium. CONCLUSIONS: Most Tx-treated patients had no pathologic endometrial changes. Endometrial polyps, hyperplasia, and metaplasia, consistent with an estrogen-agonist effect of Tx, were found in roughly one-third of all patients. The endometrial cancers were often high-grade and invasive tumors. Patients with endometrial pathology were more often symptomatic than patients with inactive/atrophic endometria.

Immunohistochemical staining of GLUT1 in benign, hyperplastic, and malignant endometrial epithelia.

BACKGROUND: Aberrant expression of the facilitative glucose transporter, GLUT1, is found in a wide spectrum of epithelial malignancies. The current study describes an immunohistochemical study of GLUT1 expression in benign, hyperplastic, and malignant endometrial epithelia. METHODS: One hundred sixteen formalin fixed, paraffin embedded sections of benign, hyperplastic, and malignant endometrial epithelium were immunostained with rabbit anti-GLUT1 antibody using the streptavidin-biotin method. RESULTS: Proliferative, secretory, and atrophic endometrium were not stained with GLUT1 antiserum. Rare, minute foci of tubal metaplasia stained positively. Simple and complex endometrial hyperplasias were consistently GLUT1 negative. All specimens of atypical hyperplasia had foci that were positive for GLUT1. All endometrial adenocarcinomas were GLUT1 positive. CONCLUSIONS: The results of the current study appear to indicate that 1) aberrant overexpression of GLUT1 is a consistent feature of endometrioid adenocarcinoma; 2) GLUT1 immunostaining may be useful in distinguishing benign hyperplasias from hyperplasias that are associated strongly with malignancy; and 3) some or all cases of atypical hyperplasia may be neoplastic rather than hyperplastic, given the existence of a molecular defect common to this hyperplastic subtype and endometrioid adenocarcinoma.

Struma ovarii and hyperthyroidism.

Struma ovarii is a teratoma of the ovaries that contains a large amount of thyroid tissue. Like the cervical thyroid gland, this ectopic thyroid tissue can become autonomous. We present a case of hyperthyroidism caused by thyroid tissue in a large ovarian cystic teratoma and provide detailed endocrinological, radiological, and pathological preoperative and postoperative data. This is also the first documented case of struma ovarii in association with a secreting pituitary tumor. In addition, we provide a retrospective pathological analysis of 1390 surgically removed ovarian tumors at 2 major academic centers.

Interphase fluorescence in situ hybridization studies of ovarian adenocarcinomas using the midisatellite probe.

The genes involved in ovarian carcinogenesis are largely unknown. Cytogenetic studies have shown a large number of chromosomal abnormalities in ovarian cancers. Molecular studies have additionally found abnormalities. Few in situ hybridization studies have been performed on ovarian cancer tissues. We chose to study the distal region of chromosome 1p with the midisatellite probe and interphase fluorescence in situ hybridization. A total of 35 patient samples, including various controls and cancers, was collected from our pathology archives. Our cancer cases included some patients with stage I disease, in whom tumors arose in endometriotic cysts. In these cases, both tumor tissue and areas in the cyst distant from the tumor mass were examined. Results showed clear cell carcinoma nuclei to have an increase in both number and size of probe signals, interpreted as representing amplification of the probed region of chromosome 1. Serous carcinomas showed an increase in the number of signals, up to four. We felt this could be a result of amplification, or, because these cells exhibited the highest mitotic counts, to DNA doubling in preparation for mitosis. Endometrioid carcinomas resembled controls in showing up to two small probe signals, but not more. We conclude that amplification in distal chromosome 1p occurs in ovarian clear cell, and possibly serous, carcinomas and may not be important in endometrioid carcinomas. Because alteration was not found in the various control epithelia, including nonmalignant-looking areas from cysts which also contained cancer, we believe that the change, when present, may not be an early step in carcinogenesis.

Gynandroblastoma in pregnancy: case report and review of literature.

Gynandroblastoma is an extremely rare tumor, composed of sex cord and stromal cells of both ovarian (granulosa-theca) and testicular (Sertoli-Leydig) types. We believe that its occurrence during pregnancy has not been previously reported. The patient was a 32-year-old woman who during her pregnancy was noted to have a progressively enlarging, unilocular left ovarian cyst. Beginning at 18 weeks gestation, the fetus required multiple platelet transfusions for severe alloimmune thrombocytopenia. A viable baby girl was delivered by cesarean section at 39 weeks gestation. At that time, an ovarian cystectomy also was performed. When the histology of the tissue subsequently became known, a left salpingo-oophorectomy was performed for gynandroblastoma. One year later, at the time of laparoscopic sterilization, the examination of the pelvis was normal.

Morphometric and electron-microscopic analyses of the effects of gonadotropin-releasing hormone agonists on uterine leiomyomas.

OBJECTIVE: Reports on the histologic effects of gonadotropin-releasing hormone agonists on uterine leiomyomas provide conflicting results. Most previous studies used qualitative methods of analysis. Using quantitative and semiquantitative stereologic methods of analysis, we assessed volume density of hyalinized areas, cell density, nuclear volume, and cytoplasmic cross-sectional areas of smooth muscle cells in histologic sections and also measured diameters of collagen fibrils in electron micrographs of uterine leiomyomas. DESIGN: Thirty leiomyomas from patients treated with gonadotropin-releasing hormone agonists (10 different patient samples), age-matched control patients (10 different patient samples), and postmenopausal women (10 different patient samples) were used. Hyalinization was assessed using a microscope with a projection head and affixed morphometric grid. Cell size and density were evaluated using a video-based, computerized system attached to the microscope, for which morphometric ad hoc programs were written. Diameters of collagen fibrils were measured from electron micrographs. SETTING: The study was conducted in the Department of Pathology, Mount Sinai Medical Center, New York, NY. PATIENTS: A total of 30 patient samples were studied, with three groups comprising 10 samples each, including patients treated with gonadotropin-releasing hormone agonists, age-matched control patients, and postmenopausal women. RESULTS: Myomas from patients treated with gonadotropin-releasing hormone agonists exhibited more hyalinization, greater cell density, slightly smaller cell sizes, and larger collagen fibrils than those of age-matched control patients and postmenopausal women. CONCLUSIONS: Shrinkage after treatment with gonadotropin-releasing hormone agonists is attributed to smaller cell size and increased collagenization in myomas.

Endometrial adenocarcinoma with choriocarcinomatous differentiation in an elderly virginal woman.

A 70-year-old virginal woman underwent hysterectomy and bilateral salpingo-oophorectomy for endometrial carcinoma. Gross examination of the surgical specimen showed normal ovaries and fallopian tubes, an enlarged uterus with several intramural leiomyomata, an endometrium completely carpeted by cancer, and, additionally, a necrotic and hemorrhagic nodular mass that protruded into the endometrial cavity. Histologic examination showed a widespread and superficially invasive, moderately differentiated endometrial adenocarcinoma that merged with a choriocarcinoma. Immunohistochemical studies showed cytoplasmic staining for human chorionic gonadotrophin in syncytiotrophoblast cells, cytotrophoblast-like cells and rare adenocarcinoma cells. A discussion of previously reported similar cases and possible mechanisms of dual differentiation in tumors, as well as comments on histogenesis are included.

Semi-automatic quantitation of nucleolar organizer regions in non-Hodgkin's lymphomas.

Nucleolar organizer regions may be useful in the diagnosis and classification of non-Hodgkin's lymphomas. In this study of 46 cases we applied morphometric analysis with quantitation of physical descriptors of the nuclear profile (area, perimeter) and both number and area of stained nucleolar organizers therein enclosed to a series of lymphomas and benign lymphoid infiltrates. While nuclear outlines were manually traced small organizer regions within the nuclear profiles were semi-automatically outlined by a thresholding procedure subjected to manual override. This results in determination of number, area and perimeter of organizer regions. Data were corrected for section thickness effects and a stereologic (three-dimensional) analysis was additionally performed. We found an increase in mean number and area of nucleolar organizers per nucleus in high grade lymphomas compared to benign infiltrates and lower grade lymphomas. Volume and thickness corrected data showed a decrease in organizer number with concomitant increase in organizer volume in the higher grade lymphomas. Multivariate analysis of the cases, previously classified histologically, showed that clear resolution could be obtained, on the basis of physical descriptors, both between as well as within groups of the three tumor grades.

Estrogen receptor variant and hypertension in women.

Eighty-eight women visiting a gynecologist were tested for an estrogen receptor B-variant allele. The women were ethnically and racially homogeneous to a large degree. They were from a suburb of Long Island, and most were white. The 12% incidence of hypertension in women with the estrogen receptor wild-type allele is comparable to the 13-32% incidence in the general population of women aged 55-64 years. However, the 48% incidence of hypertension in women with the estrogen receptor B-variant allele is considerably higher than in the general population of women in this age group. We conclude that the presence of the estrogen receptor B-variant allele might have increased the prevalence of hypertension in the women in this study.