MiR-130b modulates the invasive, migratory, and metastatic behavior of leiomyosarcoma
Danielson, Laura S; Guijarro, Maria V; Menendez, Silvia; Higgins, Brett; Sun, Qiang; Mittal, Khushbakhat; Popiolek, Dorota A; Overholtzer, Michael; Palmer, Glyn D; Hernando, Eva
Leiomyosarcoma (LMS) is an aggressive, often poorly differentiated cancer of the smooth muscle (SM) lineage for which the molecular drivers of transformation and progression are poorly understood. In microRNA (miRNA) profiling studies, miR-130b was previously found to be upregulated in LMS vs. normal SM, and down-regulated during the differentiation of mesenchymal stem cells (MSCs) into SM, suggesting a role in LMS tumor progression. In the present study, the effects of miR-130b on human LMS tumorigenesis were investigated. Stable miR-130b overexpression enhanced invasion of LMS cells in vitro, and led to the formation of undifferentiated, pleomorphic tumors in vivo, with increased growth and metastatic potential compared to control LMS cells. TSC1 was identified as a direct miR-130b target in luciferase-3'UTR assays, and shRNA-mediated knockdown of TSC1 replicated miR-130b effects. Loss-of-function and gain-of-function studies showed that miR-130b levels regulate cell morphology and motility. Following miR-130b suppression, LMS cells adopted a rounded morphology, amoeboid mode of cell movement and enhanced invasive capacity that was Rho/ROCK dependent. Conversely, miR-130b-overexpressing LMS cells exhibited Rho-independent invasion, accompanied by down-regulation of Rho-pathway effectors. In mesenchymal stem cells, both miR-130b overexpression and TSC1 silencing independently impaired SM differentiation in vitro. Together, the data reveal miR-130b as a pro-oncogenic miRNA in LMS and support a miR-130b-TSC1 regulatory network that enhances tumor progression via inhibition of SM differentiation.
Proving microcystic ultrasound appearance of borderline ovarian tumors by three-dimensional 'silhouette' rendering
Timor-Tritsch, I E; Monteagudo, A; Popiolek, D A; Duncan, K M; Goldstein, S R
Explorative Investigation of Whole-Lesion Histogram MRI Metrics for Differentiating Uterine Leiomyomas and Leiomyosarcomas
Gerges, Luke; Popiolek, Dorota; Rosenkrantz, Andrew B
OBJECTIVE:The purpose of this study is to assess the utility of texture analysis of multiple MRI sequences for the differentiation of uterine leiomyomas and leiomyosarcomas. MATERIALS AND METHODS/METHODS:Seventeen leiomyosarcomas and 51 leiomyomas undergoing MRI before resection were included. Whole-lesion volumes of interest were placed on T2-weighted images, contrast-enhanced T1-weighted images, and apparent diffusion coefficient (ADC) maps. The diagnostic performance of histogram metrics was assessed. RESULTS:achieved sensitivity of 82.4% and specificity of 74.5%. CONCLUSION/CONCLUSIONS:For whole-lesion histogram metrics obtained on various MRI sequences, T2-weighted images provided the highest, and ADC maps the lowest, performance for differentiating uterine leiomyomas and leiomyosarcomas. Metrics reflecting percentiles from the bottom half of the histogram distribution outperformed the standard mean. Models combining the T2-weighted imaging whole-lesion metrics and patient age achieved particularly high diagnostic performance. Although these findings require validation in larger studies, they have implications for facilitating improved treatment selection for these two entities.
A case of neoplastic granulosa cells in the fallopian tube, but no evidence of granulosa cell tumor
Shaw, Jacquelyn; Frey, Melissa K; Popiolek, Dorota; Ellenson, Lora Hedrick; Curtin, John P
Retrospective Assessment of Histogram-Based Diffusion Metrics for Differentiating Benign and Malignant Endometrial Lesions
Kierans, Andrea S; Doshi, Ankur M; Dunst, Diane; Popiolek, Dorota; Blank, Stephanie V; Rosenkrantz, Andrew B
OBJECTIVE: Our study aimed to retrospectively evaluate the utility of volumetric histogram-based diffusion metrics in differentiating benign from malignant endometrial abnormalities. METHODS: A total of 54 patients underwent pelvic magnetic resonance imaging with diffusion-weighted imaging before endometrial tissue diagnosis. Two radiologists placed volumes of interest on the apparent diffusion coefficient (ADC) map encompassing the entire endometrium and focal endometrial lesions. The mean ADC, percentile ADC values, kurtosis, skewness, and entropy of ADC were compared between benign and malignant abnormalities. RESULTS: In premenopausal patients, significant independent predictors of malignancy were whole-endometrium analysis for R1, 10th to 25th ADC percentile (P = 0.012); whole-endometrium analysis for R2, mean ADC (P = 0.001) and skewness (P = 0.004); focal lesion analysis for R1, skewness (P = 0.045); focal lesion analysis for R2, 10th to 25th ADC percentile (P = 0.0001). The area under the curve for malignancy was 90.0% to 97.3% and 76.1% to 77.3% for the more and less experienced radiologists, respectively. In postmenopausal patients, the only significant difference was kurtosis using whole-endometrium analysis for R1 (P = 0.042). CONCLUSIONS: Volumetric ADC histogram metrics may help radiologists assess the risk of malignancy in endometrial abnormalities on magnetic resonance imaging in premenopausal patients.
Cystadenofibromas: Can transvaginal ultrasound appearance reduce some surgical interventions?
Goldstein, Steven R; Timor-Tritsch, Ilan E; Monteagudo, Ana; Monda, Susan; Popiolek, Dorota
PURPOSE: Cystadenofibromas are benign ovarian neoplasms. Their most typical features on sonography (US) are unilocular cysts with small, shadowing hyperechoic, solid papillae without internal vascularity. In the past, they were virtually always surgically removed to exclude malignancy. This study was undertaken to review the sonographic appearances of benign cystadenomas. METHODS: We retrospectively reviewed the transvaginal US studies of 32 cases of pathologically proven ovarian cystadenofibromas. RESULTS: Twenty-two of the tumors presented as unilocular cystic structures with one or more solid, hyperechoic, shadowing, mural nodules with no discernible blood flow projecting from the inner cyst wall. Ten lesions were multiloculated with multiple small solid areas, with scant or no blood vessels. CONCLUSIONS: Cystadenofibromas do not always have a classic appearance on transvaginal US and color Doppler imaging. In our series, however, the majority (69%) presented as unilocular cysts with one or more small solid, avascular projections from the inner cyst wall. These features had 100% reliability for a diagnosis of benign cystadenofibroma in this small series. Further study is necessary to confirm the reliability of this finding for benign cystadenofibroma, thus possibly avoiding or minimizing any surgical exploration. (c) 2014 Wiley Periodicals, Inc. J Clin Ultrasound, 2014.
Cesarean scar pregnancy and early placenta accreta share common histology
Timor-Tritsch, I E; Monteagudo, A; Cali, G; Palacios-Jaraquemada, J M; Maymon, R; Arslan, A A; Patil, N; Popiolek, D; Mittal, K R
OBJECTIVE: To determine, by evaluation of histological slides, images and descriptions of early (second-trimester) placenta accreta (EPA) and placental implantation in cases of Cesarean scar pregnancy (CSP), whether these are pathologically indistinguishable and whether they both represent different stages in the disease continuum leading to morbidly adherent placenta in the third trimester. METHODS: The database of a previously published review of CSP and EPA was used to identify articles with histopathological descriptions and electronic images for pathological review. When possible, microscopic slides and/or paraffin blocks were obtained from the original researchers. We also included from our own institutions cases of CSP and EPA for which pathology specimens were available. Two pathologists examined all the material independently and, blinded to each other's findings, provided a pathological diagnosis based on microscopic appearance. Interobserver agreement in diagnosis was determined. RESULTS: Forty articles were identified, which included 31 cases of CSP and 13 cases of EPA containing histopathological descriptions and/or images of the pathology. We additionally included six cases of CSP and eight cases of EPA from our own institutions, giving a total of 58 cases available for histological evaluation (37 CSP and 21 EPA) containing clear definitions of morbidly adherent placenta. In the 29 cases for which images/slides were available for histopathological evaluation, both pathologists attested to the various degrees of myometrial and/or scar tissue invasion by placental villi with scant or no intervening decidua, consistent with the classic definition of morbidly adherent placenta. Based on the reviewed material, cases with a diagnosis of EPA and those with a diagnosis of CSP showed identical histopathological features. Interobserver correlation was high (kappa = 0.93). CONCLUSIONS: EPA and placental implantation in CSP are histopathologically indistinguishable and may represent different stages in the disease continuum leading to morbidly adherent placenta in the third trimester
Dual pten/tp53 suppression promotes sarcoma progression by activating notch signaling
Guijarro, Maria V; Dahiya, Sonika; Danielson, Laura S; Segura, Miguel F; Vales-Lara, Frances M; Menendez, Silvia; Popiolek, Dorota; Mittal, Khushbakhat; Wei, Jian Jun; Zavadil, Jiri; Cordon-Cardo, Carlos; Pandolfi, Pier Paolo; Hernando, Eva
Soft tissue sarcomas are a heterogeneous group of tumors associated with poor clinical outcome. Although a subset of soft tissue sarcomas is characterized by simple karyotypes and recurrent chromosomal translocations, the mechanisms driving cytogenetically complex sarcomas are largely unknown. Clinical evidence led us to partially inactivate Pten and Tp53 in the smooth muscle lineage of mice, which developed high-grade undifferentiated pleomorphic sarcomas, leiomyosarcomas, and carcinosarcomas that widely recapitulate the human disease, including the aberrant karyotype and metastatic behavior. Pten was found haploinsufficient, whereas the wild-type allele of Tp53 invariably gained point mutations. Gene expression profiles showed up-regulated Notch signaling in Pten(Delta/+)Tp53(Delta/+) tumors compared with Pten(+/+)Tp53(Delta/+) tumors. Consistently, Pten silencing exacerbated the clonogenic and invasive potential of Tp53-deficient bone marrow-derived mouse mesenchymal stem cells and tumor cells and activated the Notch pathway. Moreover, the increased oncogenic behavior of Pten(Delta/+)Tp53(Delta/+) and shPten-transduced Pten(+/+)Tp53(Delta/+) tumor cells was counteracted by treatment with a gamma-secretase inhibitor, suggesting that the aggressiveness of those tumors can be attributed, at least in part, to enhanced Notch signaling. This study demonstrates a cooperative role for Pten and Tp53 suppression in complex karyotype sarcomas while establishing Notch as an important functional player in the cross talk of these pathways during tumor progression. Our results highlight the importance of molecularly subclassifying patients with high-grade sarcoma for targeted treatments.
Growth patterns of placental and paraovarian adrenocortical heterotopias are different
Zhong, Hua; Xu, Bo; Popiolek, Dorota A
Two cases of adrenocortical heterotopia are reported. One is in a full-term placenta. The other is adjacent to the ovarian hilum of an adult. Both are incidental findings. Despite sharing similar histological and immunological features, they show different growth patterns. The literature is reviewed and adrenocortical heterotopias of different locations are compared. New hypotheses of its histogenesis are discussed.
Magnetic resonance imaging appearance of ovarian stromal hyperplasia and ovarian hyperthecosis [Case Report]
Rosenkrantz, Andrew B; Popiolek, Dorota; Bennett, Genevieve L; Hecht, Elizabeth M
Ovarian stromal hyperplasia and ovarian hyperthecosis are non-neoplastic conditions of the ovary associated with clinical manifestations of hyperandrogenism from ovarian production of male hormones. In this article, we present the first published cases of the magnetic resonance imaging appearance of these conditions, which may mimic that of ovarian neoplasm. In contrast to bilateral ovarian vein sampling, magnetic resonance imaging may provide a noninvasive means of suggesting a diagnosis of ovarian stromal hyperplasia/ovarian hyperthecosis when a hormone-secreting ovarian neoplasm is suspected clinically and thereby may assist in identifying patients who may be effectively treated nonsurgically with gonadotrophin-releasing hormone therapy