Endometrial Origin Research Articles

Expression of SMAD4 is Retained in Most Gynecologic Tumors with Mucinous Differentiation.

SMAD4 is a tumor suppressor gene that plays a role in cancer initiation and progression. A few studies have explored the value of immunohistochemistry for SMAD4 in gynecologic neoplasms, mainly in the ovary. However, literature is sparse when it comes to other sites such as endometrium and cervix, as well as in benign and borderline ovarian mucinous neoplasms. The aim of this study was to assess the expression of SMAD4 in various gynecologic tumors. We selected primary gynecologic tumors comprising a spectrum of neoplasms showing mucinous differentiation. Few cases of metastatic tumors were also included. A total of 103 cases were retrieved, including tumors of ovarian origin (13 mucinous adenocarcinomas, 9 mucinous borderline tumors, 19 mucinous cystadenomas, and 3 mucinous tumors arising from teratomas), 36 of endometrial origin (23 endometrioid adenocarcinomas with mucinous differentiation and 13 mucinous adenocarcinomas), 17 cases of cervical carcinoma (16 of usual type and 1 of gastric type), and 6 metastatic adenocarcinomas to ovary. SMAD4 immunohistochemistry was retained in most primary tumors, except in 3 endocervical adenocarcinomas (2 usual-type, 1 gastric-type) and in one mucinous carcinoma arising from an ovarian teratoma. Of the 6 metastatic cases, 4 showed SMAD4 loss. In summary, retained expression of SMAD4 was seen in 95.8% of primary gynecologic neoplasms. These results can be of utility when dealing with mucinous lesions for which metastatic origin is suspected. Loss of SMAD4 expression virtually excludes primary tumors of endometrial or ovarian origin, but is of less utility when evaluating carcinomas involving the cervix.

Profiles of maternal origin factors during transition from embryonic diapause to implantation in roe deer.

The aim was to evaluate in female roe deer: (a) PAG mRNA relative abundance in endometrial uterine tissue for determination of the duration of embryonic diapause, (b) mRNA relative abundance of progesterone, estradiol, and prolactin (P4, E2, and PRL) receptors (PGR, ESR, and PRLR) during diapause and after implantation in the endometrium; (c) concentration of P4, E2, and PRL in the blood, and (d) a noninvasive method of hormone detection by measurement of P4 and E2 concentrations in feces. A total of fifteen individuals were obtained post mortem during hunting seasons and divided into three experimental groups (November, December, January). The results did not reveal mRNA relative abundance for PAGs in the endometrium or detectable PAG concentrations in the serum of all examined females. Concentration of PRL and mRNA relative abundance for PRLR long isoform in the endometrium was the highest in January (p<.01). mRNA relative abundance for PGR, P4 concentration in the endometrium, serum, and feces was the highest in January (p<.01). Endometrial origin PRL and P4 may be responsible for the termination of this process and pregnancy development after implantation.

Clues to Non-Invasive Implantation Window Monitoring: Isolation and Characterisation of Endometrial Exosomes.

Despite the significant advances in the last decades, low implantation rate per transferred embryo still remains a major concern in assisted reproductive techniques, highlighting a need to better characterize endometrial receptivity also by mean of specific biomarkers. Based on physiology and on the intimate contact with endometrium as the tissue of interest, in this study we developed and validated an optimized protocol that uses extracellular vesicles (EVs) recovered from uterine flushings and from a cervical brush, the latter never used until now as an EVs source, as surrogates for endometrial biopsies. This method combines the safety of sampling with the ability to study the expression profile across the uterine cycle. We have compared the yield and composition of EVs recovered from different biofluids samples and fractions thereof, opting for chemical precipitation as the EV isolation procedure, assuring the highest yield without introducing any bias in specific EV recovery. Moreover, collected EVs, in particular exosome-like vesicles, express putative endometrial markers, such as glycodelin A and receptors for estrogen and progesterone, thus confirming their endometrial origin. We also identified uterine flushing EVs, in particular those recovered from its mucous fraction, as the richest source of endometrial transcripts, likely correlated to cellular (epithelial) origin of these vesicles. Finally, our pilot quantitative assessment of three endometrial gene profiles, in samples collected at different time points along the luteal phase, revealed the fluctuations apparently recapitulating gene expression variability prior reported during the menstrual cycle. Unlike tissue biopsy that is subjected to inter- and intra-sample differences, our data suggest that EVs from liquid biopsies (from uterine flushings and a cervical brush) obtained through less-invasive procedures, can be substrate to detect and track the tissue representative expression profiles, better depicting the total endometrium complexity.

Significance of atypical endometrial cells in women younger than 40 years of age

The presence of atypical endometrial cells in the Papanicolaou (Pap) test has been associated with an increased rate of endometrial malignancy, with reported rates ranging from 14% to 47%. However, most reported studies have focused on patients who were aged >40 years. The purpose of the present study was to investigate the clinical significance of identifying atypical endometrial cells in Pap test samples in women aged <40 years of age. A search of the cytology Pap test database was performed from 2000 to 2014 using the keywords "atypical endometrial cells" or "atypical glandular cells favor endometrial origin" in women aged <40 years. The available ThinPrep slides were reviewed. The patients' clinical presentation, follow-up endometrial biopsy findings, treatment, and clinical follow-up data were recorded. Endometrial carcinoma tissue sections were screened for Lynch syndrome. The database search yielded 63 study cases. Of these 63 patients, 52 had subsequently undergone endometrial biopsy. Of the 52 patients with follow-up biopsy findings available, 9 (17.3%) had premalignant (5 with atypical hyperplasia) or malignant (4 with endometrioid adenocarcinoma) lesions. In addition, 16 patients (30.8%) had other endometrial pathologic features. The 9 patients with premalignant or malignant endometrial lesions (8 white, 1 black) were overweight or obese; 3 of the patients did not have any clinical symptoms. All 4 patients with endometrioid adenocarcinoma had negative Lynch syndrome screening findings. Our results suggest that it is important to recognize the presence of atypical endometrial cells in the Pap tests from young patients, given its association with the finding of premalignant and malignant pathologic features in subsequent endometrial biopsies.

Secondary Tumors of the Gynecologic Tract: A Clinicopathologic Analysis.

Although the spread of extragenital tumors to individual female genital tract organs, particularly the ovary, has been much studied, histologic data with regard to secondary tumors involving the whole gynecologic tract are largely lacking. Thus, the aim of the study was to investigate the pathologic and clinical features of these tumors in order to better understand their features. This is a retrospective study of 196 secondary lesions involving the gynecologic tract. The parameters studied were the primary site, its histologic type and grade, the presence of mucous production, the type of secondary involvement, defined as distant metastasis, direct extension or locoregional recurrence, and the time to metastasis. Organs involved were the ovary (50%), the vagina (22%), the myometrium (10.7%), the cervix (10.2%), the endometrium (3.6%), the vulva (2%), and the Fallopian tube (1.5%). Most often, primary tumors were colorectal (39.8%), endometrial (15.3%), breast (12.7%), ovarian (10.7%), and gastric (5.6%). Secondary tumors were metachronous in 43.9% of the cases with a mean time to recurrence of 55.5 mo. Distant metastases were the most common type of secondary involvement (64.8%), followed by direct extension (19.9%) and local recurrence (15.3%). Gastrointestinal tumors involved mostly the ovaries, endometrial tumors the vagina, ovarian tumors the myometrium, and urothelial tumors the cervix/vagina (P<0.0001). Vaginal lesions endometrial origin presented with only superficial invasion (P=0.0002). The primary tumor's features dictate a different pattern of secondary involvement of the gynecologic tract. Endometrial tumors produce mostly superficial vaginal recurrences, mucus-producing gastrointestinal tumors present with ovarian metastases, whereas breast tumors affect the entire gynecologic tract and present the tumors with the most late recurrences.

ITRAQ comparison of proteomic profiles of endometrial receptivity

Endometrial receptivity is a limiting step in human reproduction. A disruption in the development of endometrial receptivity is responsible for recurrent implantation failures (RIF) of endometrial origin. To understand the molecular mechanisms behind the endometrial receptivity process, we used the isobaric tag for relative and absolute quantitation (iTRAQ) method to compare three different endometrial statuses: fertile women, intrauterine device (IUD) carriers, and RIF patients. Overall, iTRAQ allowed identified 1889 non-redundant proteins. Of these, 188 were differentially expressed proteins (DEP) (p-value < .05). Pairwise comparisons revealed 133 significant DEP in fertile vs. IUD carriers and 158 DEP in RIF vs. IUD carriers. However, no DEP were identified between fertile and RIF patients. Western blot validation of three DEP involved in endometrial receptivity (plastin 2, lactotransferrin, and lysozyme) confirmed our iTRAQ results. Moreover, functional KEGG enrichment revealed that complement and coagulation cascades and peroxisome were the two most significant pathways for the RIF vs. IUD comparison and ribosome and spliceosome for the fertile vs. IUD comparison, as possible important pathways involved in the endometrial receptivity acquisition. The lack of DEP between fertile and RIF patient endometria suggest that idiopathic RIF may not have an endometrial origin, with other as-yet-unknown factors involved. SignificanceA pilot study where a comparison of the endometrial protein profile from women with different endometrial receptive grade (fertile women, IUD carriers and RIF patients) during the same period of time (overlapping with the window of implantation) of a hormone replacement therapy was performed using a high-throughput proteomic technique. This approach lead us to better understand the molecular mechanisms undergoing endometrial receptivity, a time-limiting step to achieve pregnancy in humans. Moreover, the number of samples per group (10 Fertile women, 10 IUD carriers and 8 RIF patients) according to the methodology here employed (8plex iTRAQ), give more robustness to our results. Our findings confirm that an IUD introduces numerous changes in the endometrial protein profile when compared to fertile and RIF endometria, revealing some key proteins involved in endometrial receptivity. Finding no significant differences between Fertile and RIF patient endometria could suggest that other as-yet-unknown factors could be involved in the etiology of idiopathic RIF.

Overcoming Challenges in Reproductive Health Applications by Deploying More Sensitive and Accurate Molecular Technologies

The field of reproductive health is progressing rapidly from traditional non-molecular technologies based on visual microscope-based techniques to the latest molecular technologies, that are more accurate, objective, and efficient, and some of which are less invasive. Genome-wide technologies have been applied at different stages of the reproductive health lifecycle, such as preimplantation genetic testing, prenatal and postnatal testing, and preconception carrier screening. Next-generation sequencing is currently the platform of choice when it comes to preimplantation genetic testing, and analysis using cell-free DNA offers a potential non-invasive alternative to current methods. Molecular tests of endometrial receptivity identify the optimum timing for embryo implantation, thereby improving in vitro fertilisation (IVF) success rates for patients with recurrent implantation failure of endometrial origin. In the prenatal and postnatal settings, new technologies, such as microarrays and next-generation sequencing, have increased the diagnostic yield and fuelled the rate of discovery of new genetic syndromes. Expanded carrier screening panels have replaced multiple single-gene tests with a single assay and have been shown to be more effective at identifying carriers of genetic disorders. These innovations are accompanied by new challenges regarding their implementation and use. Patient access to new technologies varies greatly and several factors have been identified as barriers to uptake. Genetic counselling has become increasingly important as the amount of genetic information provided by these technologies continues to rise. This review discusses specific challenges associated with traditional non-molecular and older-generation molecular techniques in reproductive health, and suggests potential solutions provided by recent advances in genetic technologies.

Guidelines to Aid in the Distinction of Endometrial and Endocervical Carcinomas, and the Distinction of Independent Primary Carcinomas of the Endometrium and Adnexa From Metastatic Spread Between These and Other Sites.

In most cases of suspected endometrial neoplasia tumor origin can be correctly assigned according to a combination of clinical, radiologic, and pathologic features, even when the latter are based upon the examination of relatively small biopsy samples. However there are well-recognized exceptions to this rule which continue to create diagnostic difficulty, and sometimes difficulties persist even after the detailed examination of resection specimens. Among the most common problems encountered in practice are the distinction of primary endometrial and primary endocervical adenocarcinomas, and the determination of tumor origin when there is synchronous, multifocal involvement of gynecologic tract sites, for example the endometrium and the ovary. However, accurate diagnosis in these cases is important because this has significant staging, management and prognostic implications. In this review we discuss the value and limitations of key morphologic, immunophenotypic and molecular findings in these diagnostic scenarios.

Application of Bayesian network modeling to pathology informatics.

In the era of extensive data collection, there is a growing need for a large scale data analysis with tools that can handle many variables in one modeling framework. In this article, we present our recent applications of Bayesian network modeling to pathology informatics. Bayesian networks (BNs) are probabilistic graphical models that represent domain knowledge and allow investigators to process this knowledge following sound rules of probability theory. BNs can be built based on expert opinion as well as learned from accumulating data sets. BN modeling is now recognized as a suitable approach for knowledge representation and reasoning under uncertainty. Over the last two decades BN have been successfully applied to many studies on medical prognosis and diagnosis. Based on data and expert knowledge, we have constructed several BN models to assess patient risk for subsequent specific histopathologic diagnoses and their related prognosis in gynecological cytopathology and breast pathology. These models include the Pittsburgh Cervical Cancer Screening Model assessing risk for histopathologic diagnoses of cervical precancer and cervical cancer, modeling of the significance of benign-appearing endometrial cells in Pap tests, diagnostic modeling to determine whether adenocarcinoma in tissue specimens is of endometrial or endocervical origin, and models to assess risk for recurrence of invasive breast carcinoma and ductal carcinoma in situ. Bayesian network models can be used as powerful and flexible risk assessment tools on large clinical datasets and can quantitatively identify variables that are of greatest significance in predicting specific histopathologic diagnoses and their related prognosis. Resulting BN models are able to provide individualized quantitative risk assessments and prognostication for specific abnormal findings commonly reported in gynecological cytopathology and breast pathology.

Endometrial transcripts of proinflammatory cytokine and enzymes in prostaglandin synthesis are upregulated in the bitches with atrophic pyometra

Inflammatory markers of endometrial origin are valuable in order to differentiate the pyometra from cystic endometrial hyperplasia in the bitch. In the present study, we hypothesized that histological categorization would distinguish the differential regulation of the proinflammatory genes in the endometrium of bitches with pyometra. Ovariohysterectomy was done on bitches with confirmatory diagnosis of pyometra (n = 18). Using endometrium to myometrium ratio of 0.79 as threshold, the uteri (n = 8/group) were categorized into hyperplastic pyometra (HP) and atrophic pyometra (AP). Two samples were excluded as the diagnosis was inconclusive. In parallel, endometrial tissue was collected for total RNA extraction to study the differential expression of TLR4, IL-6, IL-8, COX-2 and PGFS through real time PCR. Diestrus uterus of non-pyometra bitches (n = 6) served as control. The mean fold change (2−ΔΔCt) for the target genes was determined using β-actin as endogenous control and non-pyometra uterus as calibrator group. Except TLR4, other inflammatory genes were upregulated significantly by 1.82 to 3.74 times in the AP as compared to HP with maximum upregulation of COX-2 and PGFS. Further, correlation matrix with Spearman’s rho revealed that IL-8 had strong positive correlation with COX-2 and PGFS in the AP group (P < 0.05). It is concluded that histological grading of pyometra into HP and AP revealed differential regulation of inflammatory cytokines and enzymes in the PG synthetic pathway in the canine endometrium that has diagnostic potential under clinical settings.

P1.09-40 Metastatic Endometrial Sarcoma Presenting as a Spontaneous Pneumothorax and Masquerading as a Pulmonary Blastoma

For the proper evaluation of pulmonary cavitary lesions, it is essential to obtain an adequate assessment of the patient’s clinical history. Imaging studies can be equivocal and adequate pathological diagnosis can also be challenging. This is particularly important in the case of metastatic lung tumors with extra-thoracic origin, such as certain gynecologic malignancies, which—owing to their late metastatic potential—can be noted years after removal of the primary tumor, causing a misdiagnosis. We illustrate this scenario with an interesting case of an endometrial stromal sarcoma which presented as a cavitary lesion causing a spontaneous pneumothorax and initially diagnosed as a pulmonary blastoma. 44 year old woman presented with a one day history of left sided chest pain and shortness of breath. The pain was sudden, sharp and associated with dyspnea. The patient denied any fevers, chills, cough, hemoptysis, weight loss, recent travel, sick contacts or tuberculosis. A chest X-ray demonstrated a large left-sided pneumothorax and a chest CT showed a left upper lobe cavitary lesion (Figure 1). Subsequently, a left upper lobe and lingual wedge resection were performe and biopsies of the cavitary lesion were sent. The initial pathological impression was that this was a pulmonary blastoma with heterologous leiomyosarcomatous differentiation. However, further history revealed that the patient had chronic anemia and menometrorrhagia secondary to uterine fibromas and had a total abdominal hysterectomy one year prior to presentation. This finding prompted a review of the pathological specimen and positive immunoreactivity to estrogen/progesterone receptors (ER+/PR+), and CD10+ provided the alternate diagnosis of a metastatic low-grade stromal sarcoma of endometrial origin. Patient followed with medical oncology and gynecology and is currently undergoing hormonal therapy. This case highlights the importance of a proper correlation of clinical history alongside imaging studies and immunohistochemical findings in the diagnosis of certain lung lesions, in particular thoracic gynecological malignancies.

Implantation failure of endometrial origin: what is new?

To review recent findings related to possible causes of recurrent implantation failure of endometrial origin in normal uterus. Recent evidences suggest that in apparently normal endometria, RIF may associate with molecular and functional changes in the uterus such as abnormal endometrial microbiota, including the presence of chronic endometritis, poor synchronization between the blastocyst and endometrium, and/or excessive uterine peristalsis. An altered endometrial microbiota detected by molecular techniques has been recently related to poorer embryo implantation, even in apparently normal endometria. The use of the endometrial receptivity analysis test to obtain an objective signature of endometrial receptivity has shown to improve the reproductive performance in RIF patients. The diagnosis of uterine peristalsis, however, remains challenging since the usual evaluation by transvaginal ultrasound is not accurate, and drugs tested to reduce uterine peristalsis and enhance embryo implantation have not been clearly beneficial. Finally, endometrial injury to improve implantation rates remains controversial being definitive well-designed trials needed to assess its benefit, if any. In recurrent implantation failure of endometrial origin an altered pattern of the microbial endometrial ecosystem, a displaced window of implantation leading to desynchronization between the blastocyst and the endometrium, or an altered pattern of uterine contractions during embryo transfer may be factors to consider in our attempt to solve this clinical issue. New diagnostics for assessing these conditions and new therapies to improve these dysfunctional situations are currently under investigation to be presumably included in the near future in the work-up of affected patients.

IFITM1 Outperforms CD10 in Differentiating Low-grade Endometrial Stromal Sarcomas From Smooth Muscle Neoplasms of the Uterus.

Distinguishing between uterine neoplasms of smooth muscle and endometrial stromal origin is a frequent diagnostic challenge. We investigated the staining pattern of interferon-induced transmembrane protein-1 (IFITM1), a novel endometrial stromal marker, in endometrial and smooth muscle uterine neoplasms and compared it with CD10 in its ability to differentiate between these two groups. Immunohistochemistry for IFITM1 and CD10 was performed in 20 cases of smooth muscle neoplasms (10 cases leiomyoma, 10 cases leiomyosarcoma), 14 cases of endometrial stromal sarcoma (ESS) (12 cases of low grade and 2 cases of high grade) and 12 cases of carcinosarcoma. Staining was scored in terms of intensity and distribution (0=absent, 1=weak/<50%, 2=moderate/50%-75%, 3=strong/>75%). A total score was obtained by adding intensity and distribution scores and classified as positive (score 3-6) or negative (score 0-2). IFITM1 was positive in 10 of 12 (83%) low-grade ESSs, 6 of 20 (30%) smooth muscle tumors (leiomyomas and leiomyosarcomas) and 11 of 12 carcinosarcomas (91.6%). The 2 cases of high-grade ESS were IFITM1 negative. While both IFITM1 (83%) and CD10 (91%) had high sensitivity in differentiating low-grade ESSs from smooth muscle neoplasms, IFITM1 (70%) had higher specificity compared with CD10 (45%). In this study IFITM1 appears to be a more specific marker of endometrial stromal differentiation compared with CD10 in differentiating low-grade ESSs from smooth muscle neoplasms. Thus, IFITM1 may be a valuable tool as part of an immunohistochemical evaluation panel in this diagnostic scenario.

Subcutaneous metastasis from endometrial cancer; case report and literature review

Subcutaneous metastases from endometrial cancer are rare situations, only few cases being described so far. The main incriminated mechanisms leading to the apparition of such lesions include hematogenous and lymphatic spread. We present the case of a 66-year-old patient known with previous history of stage IIIA endometroid endometrial carcinoma initially treated by surgery and adjuvant chemotherapy who developed at 18 months follow-up a distant subcutaneous oligometastasis. At this time the patient was resubmitted to surgery, the lesion being successfully removed. The histopathological result confirmed the endometrial cancer origin of this lesion. Subcutaneous and cutaneous metastases from endometrial cancer are rare eventualities which are usually diagnosed as part of systemic dissemination of this malignancy; in these cases, the patient is only candidate for oncological treatment with palliative intent. In some cases, in which the lesions occur as oligometastatic disease, surgery might be performed with curative intent. In our case the diagnostic of the subcutaneous lesion as oligometastatic disease transformed the patient in a perfect candidate for curative oncological surgery.

285 An Uncommon Presentation of Extragenital Carcinosarcoma

Carcinosarcoma, or malignant mixed Müllerian tumor, comprises less than 5% of all uterine malignancies. It is extremely uncommon to diagnose carcinosarcoma outside of the genital tract. Here, we present a 56-year-old woman who was being evaluated for an endometrial polyp. Endometrial curettage was performed. Microscopy showed fragments of an endometrial polyp with focal well differentiated endometrioid endometrial carcinoma, arising in a background of complex endometrial hyperplasia with atypia. She then underwent a total hysterectomy with bilateral salpingo-oophorectomy. Histological evaluation revealed a well differentiated endometrioid adenocarcinoma limited to the endometrium, with no protrusion into the uterine wall, extension into the adnexae, or lymphovascular invasion. At nine months status post total hysterectomy, the patient presented to her clinician with new onset vaginal bleeding, rectal bleeding. Radiological investigations revealed two 7 cm pelvic masses. Biopsy of the mass revealed highly atypical glands in a desmoplastic stroma and necrosis with features consistent with adenocarcinoma of Müllerian origin. Given the recent history of endometrial adenocarcinoma, the mass was suspected to have an endometrial origin. An exploratory laparotomy with resection of the pelvic mass, omentectomy, pelvic and para-aortic lymphadenectomies, low anterior bowel resection, ileo-cecectomy, partial vaginectomy, and left parametrial resection was performed. Histological evaluation demonstrated a fragmented carcinosarcoma; the carcinomatous component comprised predominantly endometrioid carcinoma and the sarcomatous component comprised endometrial stromal sarcoma. All lymph nodes were negative for malignancy. Immunohistochemical studies confirmed the morphological findings. Extensive sampling of the mass also showed foci of endometriosis. We present this case to highlight that a high index of suspicion and attention to morphologic details are paramount to arrive at an accurate diagnosis. It is most likely that the carcinosarcoma arose from the endometriosis rather than metastatic deposits from the previously known primary endometrioid carcinoma.

UTILITY OF INTRAPERITONEAL HYPERTHERMIC CHEMOTHERAPY IN PERITONEAL CANCER FROM ENDOMETRIAL CANCER – LITERATURE REVIEW

Once the benefits of intraperitoneal heated chemotherapy has been widely reported in patients presenting colorectal, appendicular or even ovarian malignancies, this method has been proposed as a therapeutic strategy in treating peritoneal carcinomatosis with various origins such as gastric cancer, breast cancer or even endometrial cancer. Although most often patients presenting endometrial cancer are diagnosed in an early stage of the disease and are submitted to surgery with curative intent, in certain cases the diagnostic is established only later in the evolution of the disease, when disseminated peritoneal lesions are present. In all these cases an aggressive surgical approach consisting to debulking surgery to no residual disease seems the best therapeutic option in order to achieve a good control of the disease. Moreover, it has been stipulated that association of intraperitoneal heated chemotherapy might improve the long term outcomes of such patients. This is a literature review regarding the utility of intraperitoneal heated chemotherapy in treating peritoneal carcinomatosis with endometrial origin.

Developing and validating a multivariable prediction model to improve the diagnostic accuracy in determination of cervical versus endometrial origin of uterine adenocarcinomas: A prospective MR study combining diffusion-weighted imaging and spectroscopy.

A triage test to assist clinical decision-making on choosing primary chemoradiation for cervical carcinomas or primary surgery for endometrial carcinomas is important. To develop and validate a multiparametric prediction model based on MR imaging and spectroscopy in distinguishing adenocarcinomas of uterine cervical or endometrial origin. Prospective diagnostic accuracy study. Eighty-seven women: 25 cervical and 62 endometrial adenocarcinomas divided into training (n = 43; cervical/endometrial adenocarcinomas = 11/32) and validation (n = 44; 14/30) datasets. The 3T diffusion-weighted (DW) MR imaging and MR spectroscopy. Morphology, volumetric DW MR imaging and spectroscopy (MDS) scoring system with total points 0-5, based on presence of the following MR features assessed independently by two radiologists: (a) epicenter at the cervix, (b) rim enhancement, (c) disrupted cervical stromal integrity, (d) mean volumetric apparent diffusion coefficient values (ADCmean) higher than 0.98 × 10-3 mm2 /s, (e) fatty acyl δ 1.3 ppm more than 161.92 mM. Histopathology as gold standard. Logistic regression and receiver operator characteristic (ROC) curves analysis. For both the training and validation datasets, the MDS score achieved an accuracy of 93.0% and 84.1%, significantly higher than that of morphology (88.4% and 79.5%), ADC value (74.4% and 68.2%), and spectroscopy (81.4% and 68.2%; P < 0.05 for all). The performances of the scoring were superior to the morphology in the training dataset (areas under the receiver operating characteristics curve [AUC] = 0.95 vs. 0.89; P = 0.046), but not in the validation dataset (AUC = 0.90 vs. 0.85; P = 0.289). MDS score has potentials to improve distinguishing adenocarcinomas of cervical or endometrial origin, and warrants large-scale studies for further validation. 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1654-1666.

Two candidate genes for recurrent pregnancy loss and infertility: Could ZP3 and UPK3B give us new diagnostic and therapeutic approach?

Introduction: Chromosomal indels are relatively common cytogenetic abnormalities. Nonetheless, clinical outcomes depend on the location, size and genes in deletion or duplication regions. The zona pellucida is an extracellular matrix that surrounds the oocyte and early embryo. It is composed primarily of three or four glycoproteins with various functions during fertilization and preimplantation development. The protein encoded by ZP3(Zona pellucida3) gene is a structural component of the zona pellucida and functions in primary binding and induction of the sperm acrosome reaction. UPK3B(Uroplakin 3B), a minor component of the apical plaques of mammalian urothelium that binds and dimerizes with uroplakin-1b(UPK1B), one of the major conserved urothelium membrane proteins. We herein report two cases presenting with the deletions encompassing POMZP3, UPK3B, ZP3, POM121 and POM121C genes. Case1: 25-year-old female presented to our clinic with recurrent pregnancy loss. After clinical and cytogenetic evaluation, which all of them do not feature, she was diagnosed as the deletion of POMZP3 and UPK3B genes with the array-CGH platform. (Agilent SurePrintG3 HumanCGH 60K) Case2: Ten-week embrio of 34-year-old female, infertile for ten years before and this is her first pregnancy after IVF, revealed the deletion of POM121,POM121C and ZP3 genes with the same array-CGH platform. Conclusion: We have evaluated the deletion of two consecutive genes -UPK3B and ZP3- in the genome by array-CGH analysis. Early abortion or infertility due to triploidic, tetraploidic embryos or uniparental disomy, resulting in a change in the structure of the zona pellucida with the mutations of ZP3 gene, may occur. Also mutations of UPK3B gene may cause abortion or infertility due to endometrial origin with defective function of the urothelium membrane proteins. ICSI could be a good choice for ZP3 deficient infertile woman and if PGS choosen without ICSI, uniparental disomia should be excluded.

A Rare Case of Intramural Müllerian Adenosarcoma Arising from Adenomyosis of the Uterus.

Müllerian adenosarcomas usually arise as polypoid masses in the endometrium of post-menopausal women. Occasionally, these tumors arise in the cervix, vagina, broad and round ligaments, ovaries and rarely in extragenital sites; these cases are generally associated with endometriosis. We experienced a rare case of extraendometrial, intramural adenosarcoma arising in a patient with adenomyosis. A 40-year-old woman presented with sudden-onset suprapubic pain. The imaging findings suggested leiomyoma with cystic degeneration in the uterine fundus. An ill-defined ovoid tumor with hemorrhagic degeneration, measuring 7.5 cm in diameter, was detected. The microscopic findings showed glandular cells without atypia and a sarcomatous component with pleomorphism and high mitotic rates. There was no evidence of endometrial origin. To recognize that adenosarcoma can, although rarely, arise from adenomyosis is important to avoid overstaging and inappropriate treatment.

Amplification of the NSD3-BRD4-CHD8 pathway in pelvic high-grade serous carcinomas of tubo-ovarian and endometrial origin.

Identification of novel therapeutics in pelvic high-grade serous carcinoma (HGSC) has been hampered by a paucity of actionable point mutations in target genes. The aim of the present study was to investigate the extent of amplification of the therapeutically targetable NSD3-CHD8-BRD4 pathway in pelvic HGSC, and to determine whether amplification is associated with worse prognosis. The Cancer Genome Atlas (TCGA) ovarian and endometrial cancer cohorts were retrospectively analyzed via online data-mining tools to test the association of NSD3, CHD8 and BRD4 genomic alterations with survival of pelvic HGSC patients. It was demonstrated that amplification of the NSD3-CHD8-BRD4 pathway in the ovarian HGSC cohort (observed in 18% of the cases, 88/489) was significantly associated with worse overall and progression-free survival compared with non-amplified cases. In addition, amplification of NSD3, CHD8 and BRD4 also occurred in 9% (21/232) of overall endometrial cancer TCGA cases, which was associated with worse overall survival. In the endometrial cancer TCGA cohort, NSD3, CHD8 and BRD4 amplification occurred specifically in the serous carcinoma (25%, 13/53) and 'serous-like' copy number high endometrial carcinoma (33%, 20/60) subgroups, compared with the polymerase e (0%, 0/17), microsatellite instability high (0%, 0/65) or low copy number (1%, 1/90) subgroups. These findings support the hypothesis that amplification of the NSD3-BRD4-CDH8 axis is frequent in pelvic HGSC of both ovarian and endometrial origin, and that this pathway is potentially targetable in a subset of HGSC patients.