Ulipristal Acetate Prior to Surgery for Endometriosis.

Selective progesterone receptor modulators may have a role in the treatment of endometriosis. The aim of this report is to review the effect of ulipristal acetate (UPA) on endometriosis lesions and symptoms in women treated prior to surgery. A pathology review of eutopic endometrium and endometriotic lesions was conducted by two gynecologic pathologists. The main outcome measures reported are pain reduction, amenorrhea, and pathologic progesterone receptor modulator-associated endometrial changes (PAECs). Overall, fifteen women with endometriosis received UPA over a 27-month study period. UPA was administered in an intermittent fashion in the majority of patients while 27% of patients had continuous treatment, between 6 and 24 months. Eleven (73%) patients reported amenorrhea on UPA and 11 (92%) of 12 patients with pain reported pain reduction or resolution. Fourteen patients (93%) proceeded with surgical management. Thirteen (93%) patients underwent excision of suspected endometriosis at surgery. Twelve cases (86%) had concurrent eutopic endometrium specimens and PAEC was identified in 58% (n = 7). Among the 14 cases that underwent surgery, a total of 49 extraovarian sites were sampled. Endometriosis was definitively identified in 31 (63%) of these sites. Three cases (21%) showed morphologic features similar to PAEC within foci of endometriosis. All cases of PAEC-like features in endometriosis also had PAEC in the endometrium. These patients had all noted pain reduction and amenorrhea preoperatively. In conclusion, PAECs may be found in endometriosis lesions in patients treated with UPA. Further prospective investigation is required to evaluate the efficacy and safety of SPRMs in women with endometriosis.

Metformin Abrogates Age-Associated Ovarian Fibrosis.

PURPOSE: The ovarian cancer risk factors of age and ovulation are curious because ovarian cancer incidence increases in postmenopausal women, long after ovulations have ceased. To determine how age and ovulation underlie ovarian cancer risk, we assessed the effects of these risk factors on the ovarian microenvironment. EXPERIMENTAL DESIGN: Aged C57/lcrfa mice (0-33 months old) were generated to assess the aged ovarian microenvironment. To expand our findings into human aging, we assembled a cohort of normal human ovaries (n = 18, 21-71 years old). To validate our findings, an independent cohort of normal human ovaries was assembled (n = 9, 41-82 years old). RESULTS: We first validated the presence of age-associated murine ovarian fibrosis. Using interdisciplinary methodologies, we provide novel evidence that ovarian fibrosis also develops in human postmenopausal ovaries across two independent cohorts (n = 27). Fibrotic ovaries have an increased CD206+:CD68+ cell ratio, CD8+ T-cell infiltration, and profibrotic DPP4+αSMA+ fibroblasts. Metformin use was associated with attenuated CD8+ T-cell infiltration and reduced CD206+:CD68+ cell ratio. CONCLUSIONS: These data support a novel hypothesis that unifies the primary nonhereditary ovarian cancer risk factors through the development of ovarian fibrosis and the formation of a premetastatic niche, and suggests a potential use for metformin in ovarian cancer prophylaxis.See related commentary by Madariaga et al., p. 523.

Preeclampsia is a biomarker for vascular disease in both mother and child: the need for a medical alert system.

This paper reviews the literature pertaining to the impact of preeclampsia not only on the mother but particularly on the children. The review points to the higher blood pressure in children born to preeclamptic mothers compared to controls, their increased tendency to suffer strokes, the reduction in their cognitive ability, and their vulnerability to depression. Mechanisms that may induce these changes are emphasized, particularly the placental vascular insufficiency and the resulting hypoxic and proinflammatory environments in which the fetus develops. The hypothesis proposed is that these changes in the fetal-placental environment result in epigenetic programming of the child towards a higher propensity for vascular disease. The review's main recommendation is that, within ethical boundaries, the medical records of individuals born to preeclamptic mothers should clearly indicate this event and should be made available to the affected individuals so that preventive measures against vascular complications and lifestyle changes that may mitigate the latter can be instituted.

Induction of a menopausal state alters the growth and histology of ovarian tumors in a mouse model of ovarian cancer.

OBJECTIVE: Ovarian cancer is often diagnosed in women after menopause when the levels of the serum gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are increased because of the depletion of growing follicles within the ovary. The ability of FSH and LH to modulate the disease has not been well studied owing to a lack of physiologically relevant models of ovarian cancer. In this study, 4-vinylcyclohexene diepoxide (VCD) was used to deplete ovarian follicles and increase the levels of circulating FSH and LH in the tgCAG-LS-TAg mouse model of ovarian cancer. METHODS: VCD-induced follicle depletion was performed either before or after induction of the oncogene SV40 large and small T-antigens in the ovarian surface epithelial cells of tgCAG-LS-TAg mice, which was mediated by the intrabursal delivery of an adenovirus expressing Cre recombinase (AdCre). RESULTS: tgCAG-LS-TAg mice injected with AdCre developed undifferentiated ovarian tumors with mixed epithelial and stromal components and some features of sex cord stromal tumors. Treatment with VCD before or after AdCre injection yielded tumors of similar histology, but with the unique appearance of Sertoli cell nests. In mice treated with VCD before the induction of tumorigenesis, the ovarian tumors tended to grow more slowly. The human ovarian cancer cell lines SKOV3 and OVCAR3 responded similarly to increased levels of gonadotropins in a second model of menopause, growing more slowly in ovariectomized mice compared with cycling controls. CONCLUSIONS: These results suggest that follicle depletion and increased gonadotropin levels can alter the histology and the rate of growth of ovarian tumors.

17beta-estradiol accelerates tumor onset and decreases survival in a transgenic mouse model of ovarian cancer.

Epithelial ovarian cancer is thought to be derived from the ovarian surface epithelium (OSE) but often goes undetected in the early stages, and as a result, the factors that contribute to its initiation and progression remain poorly understood. Epidemiological studies have suggested that the female steroid hormones are involved in ovarian carcinogenesis and that women who use hormone replacement therapy are at increased risk of developing the disease. A novel transgenic mouse model of ovarian cancer (tgCAG-LS-TAg) was developed to examine the role of the female reproductive steroid hormones [17beta-estradiol (E(2)) and progesterone (P(4))] on the initiation, progression, and pathology of ovarian cancer. The mouse model uses the Cre-LoxP system to induce expression of the simian virus 40 large and small T antigens (SV40 TAg). After targeted induction of the oncogene in the OSE, mice develop poorly differentiated ovarian tumors, tumor dissemination to tissues within the abdominal cavity, and a subset develops hemorrhagic ascites. Treatment with P(4) had no impact on the disease, but E(2) altered the pathophysiology, resulting in an earlier onset of tumors, decreased overall survival time, and a distinctive papillary histology. Normal ovaries collected from mice treated with E(2), but lacking expression of SV40 TAg, displayed an increase in the areas of columnar and hyperplastic OSE cells compared to placebo-treated controls. A better understanding of the mechanisms by which E(2) alters the morphology of normal OSE cells and reduces survival in this mouse model may translate into improved prevention and treatment options for women using hormone replacement therapy.

Mullerian adenosarcoma of the cervix in a 10-year-old girl: case report and review of the literature.

UNLABELLED: Müllerian adenosarcoma is a rare neoplasm usually found in postmenopausal women. It usually presents as a polypoid mass within the endometrium. It is a biphasic tumor, composed of a benign epithelial component and a malignant stromal component. To date, this neoplasm has been reported in only 16 adolescent girls. We present a case of a 10-year-old girl who was diagnosed with müllerian adenosarcoma arising from the endocervix, the youngest female ever reported. CASE REPORT: A 10-year-old previously healthy girl presented to the Emergency Department at the Children's Hospital of Eastern Ontario with a painless mass protruding from her vagina. She had experienced mild vaginal bleeding for two weeks prior to her presentation. On physical examination, her vital signs were stable, and pubertal development was Tanner III breast and Tanner II pubic development. Rectoabdominal examination was negative. Two polypoid lesions were seen protruding past the hymenal ring and were removed in the emergency department. On gross examination, they were a dark tan color and had a fleshy appearance with a gelatinous consistency. They measured 5.5 x 1.5 x 1.0 cm and 3.5 x 1.5 x 1.5 cm. The final pathology revealed müllerian adenosarcoma, favoring an endocervical origin. Further investigations, including an abdominal/pelvic ultrasound and MRI and chest radiography, were negative. The patient subsequently underwent examination under anesthesia, vaginoscopy, hysteroscopy, polypectomy, and dilatation and curettage. The vagina appeared normal. At the level of the cervix, there were 3 polypoid gelatinous structures arising from the endocervix and extruding past the exocervix. They measured 0.8 x 0.5 x 0.2 cm up to 1.1 x 0.7 x 0.5 cm. The lesions were removed. Hysteroscopic inspection of the uterine cavity did not find any abnormalities. An endometrial curettage was performed. Pathology confirmed a diagnosis of müllerian adenosarcoma originating from the endocervix. Uterine curettings were negative for malignancy. After a thorough evaluation of the available literature, review with the Regional Tumor Board and extensive discussions with the family, a decision was made to perform a radical hysterectomy, bilateral salpingectomy, bilateral pelvic lymph node dissection, upper vaginectomy and preservation of ovaries. The procedure was uncomplicated. Clinically, there was no evidence of residual disease. The final pathology was negative for malignancy. CONCLUSION: Müllerian adenosarcoma of the endocervix is a very rare pediatric tumor. Due to the rarity of this tumor in this age group, optimal therapy is uncertain. Most experts recommend hysterectomy. The review of literature reveals a high recurrence rate following conservative surgical management. Chemotherapy and radiation have not been used in the absence of extensive pelvic and/or residual disease. Poor prognostic factors include depth of invasion, sarcomatous overgrowth and high-grade malignant features in the stromal component. If recurrence occurs, it tends to be local and following prior conservative treatments such as cone biopsy or trachelectomy. Recurrences may occur late and thus long term follow-up of these patients is recommended.

Cytologic features of benign solitary pulmonary nodules with radiologic correlation and diagnostic pitfalls: a report of six cases.

BACKGROUND: The solitary pulmonary nodule (SPN) is a common radiologic abnormality often detected incidentally. The majority of SPNs represent benign processes, including granulotmatous inflammation, bronchogenic cysts and hamartomata. However, a solitary nodule may also potentially represent an early stage of lung cancer or a metastasis. Diagnostic procedures such as percutaneous fine needle aspiration biopsy can exclude malignancy in a majority of cases and may eliminate the need for more invasive surgical procedure. Correlation of the findings on the FNAB with radiologic features is helpful in establishing the benignity. CASES: We report the cytologic features of 6 cases of benign SPN: exogenous lipid pneumonia, sclerosing hemangioma, hemartoma, bronchogenic cyst, fungal granuloma and solitary fibrous tumor. We provide radiologic correlation for each entity and discuss the diagnostic pitfalls. CONCLUSION: Cytologically, lack of nuclear atypia with bland chromatin is useful in separating benign from malignant SPN. Radiologically, smaller lesions with smooth, well-defined margins and calcifications are more likely to be benign. Our cases illustrate the cytologic and immunohistochemical features that can help to make a more precise diagnosis. The identification of these features, when correlated with imaging findings, allows the cytopathologist to better approach the SPN.

Conditional inactivation of Brca1, p53 and Rb in mouse ovaries results in the development of leiomyosarcomas.

Epithelial ovarian cancer (EOC) is thought to arise in part from the ovarian surface epithelium (OSE); however, the molecular events underlying this transformation are poorly understood. Germline mutations in the BRCA1 tumor suppressor gene result in a significantly increased risk of developing EOC and a large proportion of sporadic EOCs display some sort of BRCA1 dysfunction. To generate a model in which Brca1-mediated transformation can be studied, we previously inactivated Brca1 alone in murine OSE, which resulted in an increased accumulation of premalignant changes, but no tumor formation. In this study, we examined tumor formation in mice with conditionally expressed alleles of Brca1, p53 and Rb, alone or in combination. Intrabursal injection of adenovirus expressing Cre recombinase to inactivate p53 resulted in tumors in 100% of mice. Tumor progression was accelerated in mice with concomitant inactivation of Brca1 and p53, but not Rb and p53. Immunohistologic analyses classified the tumors as leiomyosarcomas that may be arising from the ovarian bursa. Brca1 inactivation in primary cultures of murine OSE cells led to a suppression of proliferation that could be rescued by concomitant inactivation of p53 and/or Rb. Brca1-deficient OSE cells displayed an increased sensitivity to the DNA damaging agent cisplatin, and this effect could be modulated by inactivation of p53 and/or Rb. These results indicate that Brca1 deficiency can accelerate tumor development and alter the sensitivity of OSE cells to chemotherapeutic agents. Intrabursal delivery of adenovirus intended to alter gene expression in the ovarian surface epithelium may, in some strains of mice, result in more rapid transformation of adjacent cells, resulting in leiomyosarcomas.

Phase II evaluation of imatinib mesylate in the treatment of recurrent or persistent epithelial ovarian or primary peritoneal carcinoma: a Gynecologic Oncology Group Study.

PURPOSE: This phase II trial assessed the activity and tolerability of an oral dose of imatinib mesylate 400 mg twice daily in patients with recurrent or persistent epithelial ovarian or primary peritoneal carcinoma. The association between the expression of certain markers and clinical outcome was investigated. PATIENTS AND METHODS: Primary measure of clinical efficacy was progression-free survival (PFS) at 6 months. Mutational analysis of KIT, immunohistochemistry (IHC) and enzyme-linked immunosorbent assay for markers (KIT, platelet-derived growth factor [PDGF] receptor [-R], AKT2, phosphorylated AKT [p-AKT], stem cell factor [SCF], and PDGF) were performed. RESULTS: Fifty-six eligible patients were evaluated. Nine patients were progression free for at least 6 months including one complete responder. The median PFS and survival were 2 and 16 months, respectively. The most common grade 3 and 4 toxicities were neutropenia, GI, dermatologic effects, pain, and electrolyte disturbances. At least one target of imatinib (KIT, PDGFR-alpha, or PDGFR-beta) was expressed in all tumors, and most tumors expressed all three receptors. Higher expression of p-AKT and PDGFR-beta were associated with shorter PFS, and higher IHC scores (% immunopositive cells x staining intensity) of SCF and p-AKT were associated with decreased overall survival. No sequence mutations were detected in the KIT gene. Higher pretreatment plasma concentrations of PDGF-AB, PDGF-BB, and vascular endothelial growth factor (VEGF) were individually associated with shorter PFS and survival. CONCLUSION: Imatinib mesylate was well tolerated but had minimal single-agent activity in patients with recurrent ovarian or primary peritoneal carcinoma. No marker was identified that would predict activity of imatinib; however, tumor p-AKT and plasma VEGF levels were associated with poor outcome.

Atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion: cytohistologic correlation study with diagnostic pitfalls.

OBJECTIVE: In the current study, we explore the diagnostic parameters and pitfalls in the follow-up of 123 cases of Pap smears diagnosed as high-grade atypical squamous cells (ASC-H) at our institution. STUDY DESIGN: A computer database search was performed from the archives of the Ottawa Hospital Cytopathology Service for cases diagnosed with ASC-H between January 2003 and July 2005. RESULTS: Follow-up of the 123 cases of ASC-H showed high grade squamous intraepithelial lesion (HSIL) in 73 patients (59.4%), low grade squamous intraepithelial lesion (LSIL) in 11 (8.9%), immature squamous metaplasia in 23 (18.7%), reactive squamous cell changes in 12 (9.8%), benign glandular lesions (endocervical atypia, degenerated glandular cells) in 2 (1.6%) and atrophy in 2 (1.6%). In our study, 83 patients were younger than 40 years (67.4%), with biopsy-proven HSIL found in 54 patients (65.1%). The remaining 40 patients (32.6%) were older than 40 years of age, and follow-up biopsies showed HSIL in 19 patients (47.5%). CONCLUSION: In our study, 59.4% of the cases that were diagnosed cytologically as ASC-H were found to have HSIL on subsequent biopsies. This correlation was stronger in patients below the age of 40 years (65.1% vs. 47.5%). The cytopathologic feature most strongly associated with HSIL was the presence of coarse nuclear chromatin (84%).

Omental chemotherapy effects as a prognostic factor in ovarian cancer patients treated with neoadjuvant chemotherapy and delayed primary surgical debulking.

BACKGROUND: We sought to assess the prognostic significance of chemotherapy effect on upper abdominal metastatic disease. METHODS: Retrospective chart reviews were carried out from 1997 to 2005 to identify ovarian cancer patients treated with neoadjuvant chemotherapy. Pathologic examinations of resected omental and ovarian tumors for the presence of chemotherapy effect were performed. Cox proportional hazard models were built to model time to progression and death by using predictor variables of age, tumor grade, amount and location of largest residual disease, and the presence of chemotherapy effects on resected tumors. RESULTS: Sixty-six patients with available slides and clinical information were identified. The presence of omental chemotherapy effects was observed in 58 patients (88%). Identified independent statistically significant predictors for progression-free survival included presence of omental chemotherapy effect (hazard ratio [HR], .38; 95% confidence interval [95% CI], .17-.89; P = .026) and suboptimal tumor residuals in upper abdominal location compared with pelvic location (HR, 2.41; 95% CI, 1.06-5.48; P = .035). The presence of omental chemotherapy effect was the only statistically significant predictor of disease specific survival (HR, .21; 95% CI, .068-.639; P = .006). The estimated median survival for the group with positive omental chemotherapy effect was 84.45 months (95% CI, 69.63-99.28). The corresponding statistic in patients with no observed response to chemotherapy was 31.15 months (95% CI, 21.84-40.47). CONCLUSIONS: Upper abdominal disease location and its response to chemotherapy were independent prognostic factors for progression-free survival. Aggressive upper abdominal debulking procedures are recommended to improve oncologic outcomes.

Palliative radiotherapy for recurrent granulosa cell tumor of the ovary: a report of 3 cases with radiological evidence of response.

BACKGROUND: The role of radiotherapy for recurrent or residual granulosa cell tumor of the ovary (GCTO) is controversial. One reason for this controversy may be that most published studies on this topic have not utilized sectional imaging to assess response to radiotherapy. We report on three cases of recurrent or residual GCTO that were treated with radiotherapy for which pre- and post-treatment CT scans were available to assess response. CASE REPORTS: Case #1: A 77-year-old woman with a 7 x 10-cm pelvic mass post-surgery was treated with radiotherapy to a dose of 45 Gy in 25 fractions followed by a boost of 10 Gy in 5 fractions. Post-treatment scans revealed a decrease in tumor size to 4 x 2.5 cm. The reduction in tumor volume was 86%, and the duration of response was 13 months. Case #2: A 73-year-old woman with multiple abdominal recurrences was treated with radiotherapy to a dose of 30 Gy in 20 fractions. The dominant mass shrank from 13 x 17 cm to 5.1 x 6.6 cm. The reduction in volume was 85%, and the duration of response has been 5 months. Her symptom of abdominal bloating and early satiety abated. Case #3: An 83-year-old woman with a 20 x 20 x 15-cm mass in the left abdomen was treated with radiotherapy to a dose of 45 Gy in 25 fractions. The mass decreased in size to 3.7 x 2.5 cm post-treatment. The duration of response has been 21 months. Her symptom of left leg swelling disappeared after therapy. CONCLUSION: Radiotherapy is highly effective in treating recurrent or residual GCTO. In these three cases, the tumor volume decreased by 85 to 90%, and the duration of response has, up to now, been 5 to 21 months.

Characterization of intraperitoneal, orthotopic, and metastatic xenograft models of human ovarian cancer.

Improvement of ovarian cancer patient outcome requires well-characterized animal models in which to evaluate novel therapeutics. Xenograft models are frequently used, but with little discussion of disease histology. The objectives of this study were to inject 11 ovarian cancer cell lines intraperitoneally (ip), and a subset intrabursally (ib; orthotopic), into nude mice and to analyze the resulting pathologies. Eight of 11 lines injected ip formed tumors within 3 months at variable rates with the following histological subtype distribution: one endometrioid, one serous, one clear cell, and five undifferentiated. Only mice injected with A2780-cp cells presented with ovarian-specific metastases (11 of 88), and the survival time of these animals was significantly shorter, which may be attributed to the higher proliferation rate as determined by Ki67 positivity. Additional analysis of the influence of the ovarian microenvironment on cell characteristics was conducted with ib injection of two cell lines (OVCA 429 and ES-2). The site of injection did not affect the tumor histology, the effect on proliferation was cell-type dependent, and the tumor take rate (cell survival) was negatively affected for OVCA 429 cells. The animal models described herein represent histologically distinct models of both early and late stage ovarian cancer useful for evaluation of therapeutics.

Assessment of two alternative sample transport and fixation methods in the microbiological diagnosis of bacterial vaginosis.

BACKGROUND: The standard method for specimen collection and transport for microbiological diagnosis of bacterial vaginosis is an air-dried smear of vaginal secretions, promptly heat- or alcohol-fixed, Gram-stained and scored by Nugent's criteria. OBJECTIVE: TWO ALTERNATIVE METHODS ARE EVALUATED: sending a swab in transport medium to be smeared and Gram-stained in the laboratory two days later; and sending a smear of vaginal secretions sprayed with cytological fixative to the laboratory for Gram staining seven days later. METHODS: One hundred fifty-two women aged 18 years and older who attended a hospital colposcopy clinic or a community healthy sexuality clinic were studied. This was a prospective study: three vaginal swabs were taken from each patient and handled as described above. Each slide was blindly and independently interpreted by two microbiology technologists. The sensitivity, specificity and coefficient of agreement of the transported swab and cytologically fixed methods were compared with the air-dried smear method. RESULTS: Smears from swabs in transport medium and cytologically fixed smears both had 90% sensitivity and 97% specificity for bacterial vaginosis compared with diagnosis from air-dried smears. Cohen's kappa was 0.88 (95% CI 0.79 to 0.97) for each method. Inter-rater reliability assessed over all slides (all sampling techniques) was excellent (kappa 0.94). CONCLUSIONS: For the diagnosis of bacterial vaginosis, both alternative techniques provide results equivalent to air-dried direct smears. A vaginal smear sprayed with cytological fixative provides immediate fixation of material to the slide, permits delays in swab transport and avoids the requirement for transport at a controlled temperature imposed by swabs.

Detailed account of confounding factors in interpretation of FTIR spectra of exfoliated cervical cells.

The confounding variables that can potentially lead to a misinterpretation of FTIR spectroscopy of exfoliated cervical cells is described. A detailed account of the spectral effects of the following variables in FTIR spectroscopic screening of exfoliated cervical cells is presented: polymorphs; Cell degradation; and impurities such as endocervical columnar cells, metaplastic cells, cervical mucus, red cells, and debris. The interpretation of the spectra of exfoliated cervical cells must be done with subtraction analysis, which includes these factors. This is essential to prevent unacceptable false-positive rates. The above techniques are subsequently applied to two clinic populations: a dysplasia clinic in follow-up patients with negative cytology and two general gynecology clinics with patients with negative cytology. In the dysplasia clinic group 250 sequential patients with negative smears were tested. Thirty had false-positive smears as defined by the IR spectroscopy using the above methodology. Twenty of those patients subsequently had one follow-up and six had a positive abnormal smear. In the community clinic group 656 sequential patients were examined who had negative smears, of which 27 had false-positive FTIR spectra.