Inhibition of CSF1R and KIT With Pexidartinib Reduces Inflammatory Signaling and Cell Viability in Endometriosis.

Endometriosis is a common and debilitating disease, affecting ∼170 million women worldwide. Affected patients have limited therapeutic options such as hormonal suppression or surgical excision of the lesions, though therapies are often not completely curative. Targeting receptor tyrosine kinases (RTKs) could provide a nonhormonal treatment option for endometriosis. We determined that 2 RTKs, macrophage-colony stimulating factor 1 receptor (CSF1R) and mast/stem cell growth factor receptor KIT (KIT), are overexpressed in endometriotic lesions and could be novel nonhormonal therapeutic targets for endometriosis. The kinase activity of CSF1R and KIT is suppressed by pexidartinib, a small molecule inhibitor that was recently approved by the US Food and Drug Administration. Using immunohistochemistry, we detected CSF1R and KIT in endometriotic tissues obtained from peritoneal lesions, colorectal lesions, and endometriomas. Specifically, we show that KIT is localized to the epithelium of the lesions, while CSF1R is expressed in the stroma and macrophages of the endometriotic lesions. Given the high epithelial expression of CSF1R and KIT, 12Z endometriotic epithelial cells were used to evaluate the efficacy of dual CSF1R and KIT inhibition with pexidartinib. We found that pexidartinib suppressed activation in 12Z cells of JNK, STAT3, and AKT signaling pathways, which control key proinflammatory and survival networks within the cell. Using quantitative real-time polymerase chain reaction, we determined that pexidartinib suppressed interleukin 8 (IL8) and cyclin D1 (CCND1) expression. Lastly, we demonstrated that pexidartinib decreased cell growth and viability. Overall, these results indicate that pexidartinib-mediated CSF1R and KIT inhibition reduces proinflammatory signaling and cell viability in endometriosis.

Proteogenomic insights suggest druggable pathways in endometrial carcinoma.

We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted quantitation of two peptides can predict antigen processing and presentation machinery activity, and may inform patient selection for immunotherapy. Association analysis between MYC activity and metformin treatment in both patients and cell lines suggests a potential role for metformin treatment in non-diabetic patients with elevated MYC activity. PIK3R1 in-frame indels are associated with elevated AKT phosphorylation and increased sensitivity to AKT inhibitors. CTNNB1 hotspot mutations are concentrated near phosphorylation sites mediating pS45-induced degradation of ß-catenin, which may render Wnt-FZD antagonists ineffective. Deep learning accurately predicts EC subtypes and mutations from histopathology images, which may be useful for rapid diagnosis. Overall, this study identified molecular and imaging markers that can be further investigated to guide patient stratification for more precise treatment of EC.

Herpesvirus Infection Masquerading as a Neoplasm in an HIV-Positive Patient: A Potential Diagnostic Pitfall.

ABSTRACT: Herpesvirus infection classically presents as a clustered, vesicular rash over mild erythema. However, unusual presentations may mimic tumors and be a potential pitfall. We describe the case of a 55-year-old HIV positive woman with this unusual manifestation of a common disease which was initially diagnosed as a benign neoplasm. Review of pathology revealed histologic features characteristic of this form of herpesvirus eruption. Awareness of this rare clinical and microscopic presentation is important to guide appropriate use of immunostains, prevent misdiagnosis, and promptly institute of antiviral therapy.

SMAD2/3 signaling in the uterine epithelium controls endometrial cell homeostasis and regeneration.

The regenerative potential of the endometrium is attributed to endometrial stem cells; however, the signaling pathways controlling its regenerative potential remain obscure. In this study, genetic mouse models and endometrial organoids are used to demonstrate that SMAD2/3 signaling controls endometrial regeneration and differentiation. Mice with conditional deletion of SMAD2/3 in the uterine epithelium using Lactoferrin-iCre develop endometrial hyperplasia at 12-weeks and metastatic uterine tumors by 9-months of age. Mechanistic studies in endometrial organoids determine that genetic or pharmacological inhibition of SMAD2/3 signaling disrupts organoid morphology, increases the glandular and secretory cell markers, FOXA2 and MUC1, and alters the genome-wide distribution of SMAD4. Transcriptomic profiling of the organoids reveals elevated pathways involved in stem cell regeneration and differentiation such as the bone morphogenetic protein (BMP) and retinoic acid signaling (RA) pathways. Therefore, TGFß family signaling via SMAD2/3 controls signaling networks which are integral for endometrial cell regeneration and differentiation.

Ichthyosis uteri: A keratinizing squamous metaplasia of the endometrium with premalignant potential.

•Ichthyosis uteri is a rare condition describing extensive endometrial keratinization.•There may be an association with squamous cell carcinoma of the endometrium.•Endometrial extension of cervical malignancy may closely resemble ichthyosis.•A hysterectomy should be considered in patients who have completed childbearing.

Isolated Metastasis to Fallopian Tube Mucosa by Low-Grade Appendiceal Mucinous Neoplasm: Report of Two Cases.

Isolated metastases from non-gynecological cancers to the fallopian tube are rare. Recent literature suggests that mucosal alterations of the fallopian tube should be considered primary tubal lesions. This has led to a paradigm shift in the classification of ovarian tumors with studies proposing tubal origin for these tumors, and clinicians advocating distal salpingectomy to decrease rates of ovarian cancer. This is based on the theory that sole presence of tubal mucosal disease is evidence of tubal origin. We present two patients with isolated mucosal metastases to the fallopian tube from appendiceal tumors. Two 36- and 72-year-old women presented with adnexal masses. Both had a history of right hemicolectomy for low-grade appendiceal mucinous neoplasms. The tubes in both cases were distended with mucin. Microscopic examination showed multifocal low-grade mucinous epithelium with papillations and tufting, interspersed by normal tubal epithelium. The mucinous epithelium was diffusely positive for keratin 20 and CDX2, focally positive for keratin 7, and negative for ER and PAX8 in both cases. Ovaries showed acellular mucin pools. Based on morphology and immunohistochemical features, it is likely that these tumors are of primary appendiceal origin metastatic to fallopian tube mucosa. These cases are unique in that no other organs were involved by metastases raising the possibility of an in-situ lesion or benign tubal mucinous metaplasia. These cases bring up an important point that mucosal metastasis can occur and question the current practice of assigning primary origin of a tumor to the fallopian tube in the presence of "intraepithelial" tumor.

Epithelioid Trophoblastic Tumor Presenting as an Adnexal Mass: Report of a Diagnostically Challenging Case.

Epithelioid trophoblastic tumor (ETT) is a rare neoplasm derived from chorionic intermediate trophoblast cells, representing less than 2% of all gestational trophoblastic neoplasms. Classically, ETT presents as a uterine mass in women of reproductive age following a term pregnancy. The time from pregnancy to tumor development varies from months to several years. ETT most often arises in the endometrium, followed by the cervix. Extrauterine ETT are extremely infrequent, with few cases reported in the literature. We report a case of a 41-year-old woman, with history of three term pregnancies who presented with abdominal pain and elevated beta human chorionic gonadotropin (ß-hCG) level, ten years after her last pregnancy. Imaging reported a 3.5 cm adnexal mass, suspicious for ectopic pregnancy. Hysterectomy and mass resection revealed a 4.7 cm, tan-yellow, necrotic mass adjacent to the broad ligament. Histologic evaluation in conjunction with immunohistochemical stains revealed a tumor consistent with ETT. No connection to the endometrium was found grossly or microscopically. DNA fingerprinting analysis revealed the tumor to have two copies of paternal alleles, as seen in molar gestations. One of the primary differential diagnoses for ETT is squamous cell carcinoma due to similar morphologic features. In challenging cases, genetic analysis demonstrating paternally derived genes can establish the diagnosis. In this report, we discuss the challenges in the diagnosis of extrauterine ETT, due to its rarity and highly variable presentation, given that appropriate diagnosis is critical for correct patient management.

Unusual case of uterine intravascular leiomyomatosis with lymphatic spread to pelvic lymph nodes.

Intravascular leiomyomatosis is a rare disease characterized by extension of benign smooth muscle proliferation into uterine and pelvic vessels. The involved vessels are almost always veins and rarely lymphatics. Intraarterial growth has not been described. Intravascular leiomyomatosis can show different morphologic features that are commonly described in leiomyomas. The differential diagnosis includes endometrial stromal sarcoma, lymphangioleiomyomatosis and leiomyosarcoma. Immunohistochemistry is helpful to establish a correct diagnosis. The condition is histologically benign; however, these lesions can spread by the venous system into the inferior vena cava, heart, and lungs. Treatment of this condition is surgical. The spread of intravenous leiomyomatosis exclusively by uterine lymphatics to the pelvic lymph nodes has not been previously reported.

Lack of uniformity in reporting autoimmune gastritis among a diverse group of pathologists.

Autoimmune gastritis (AIG) is a clinicopathologic diagnosis requiring characteristic histopathology and correlation with laboratory work-up. To better understand how the diagnosis of AIG is made and reported in the pathology community, we conducted an anonymous web-based survey which was circulated among a diverse group of pathologists. Excluding trainees there were 64 respondents: 25 academic gastrointestinal pathologists (AGI, 39%), 22 academic general pathologists (AGP, 34%), 17 private general pathologists (PP, 27%). Our survey results highlighted variations in work-up and sign-out practices. The type of metaplasia needed to diagnose AIG lacked consensus. There was variation in accurate interpretation of immunostains with a trend towards more accurate diagnosis of enterochromaffin-like (ECL) cell hyperplasia by AGI (92%) and AGP (95%) than PP (71%) (p = 0.07). G-cells in antrum on neuroendocrine immunostain, a mimicker of ECL cell hyperplasia, was more frequently misdiagnosed by PP/ AGP (44%), versus AGI (12%) (p = 0.02). A triple immunostain panel (H. pylori, neuroendocrine, gastrin) was used in the work-up of AIG by 72% of AGI versus 23% AGP and 12% PP (p = 0.000061). The less-specific term "atrophic gastritis" was used in the diagnostic line more by respondents with >10 years sign-out experience compared with others (p = 0.04). In conclusion, the survey results highlighted deficiencies in the interpretation of neuroendocrine immunostains which is crucial for AIG diagnosis, as well as variation in reporting practices and definitions. Uniform criteria and terminology are needed in this field to improve communication with clinicians, resulting in appropriate testing and follow-up.

Endometrial receptivity and implantation require uterine BMP signaling through an ACVR2A-SMAD1/SMAD5 axis.

During early pregnancy in the mouse, nidatory estrogen (E2) stimulates endometrial receptivity by activating a network of signaling pathways that is not yet fully characterized. Here, we report that bone morphogenetic proteins (BMPs) control endometrial receptivity via a conserved activin receptor type 2 A (ACVR2A) and SMAD1/5 signaling pathway. Mice were generated to contain single or double conditional deletion of SMAD1/5 and ACVR2A/ACVR2B receptors using progesterone receptor (PR)-cre. Female mice with SMAD1/5 deletion display endometrial defects that result in the development of cystic endometrial glands, a hyperproliferative endometrial epithelium during the window of implantation, and impaired apicobasal transformation that prevents embryo implantation and leads to infertility. Analysis of Acvr2a-PRcre and Acvr2b-PRcre pregnant mice determined that BMP signaling occurs via ACVR2A and that ACVR2B is dispensable during embryo implantation. Therefore, BMPs signal through a conserved endometrial ACVR2A/SMAD1/5 pathway that promotes endometrial receptivity during embryo implantation.

Brenner tumor associated with rete ovarii: a histologic and immunohistochemical analysis of six cases exploring the relationship between these entities.

The association of Brenner tumor (BT) with rete ovarii (RO) has been rarely alluded to in the literature. Both entities have debatable histogenesis. In this study of six cases of BT associated with RO, we describe the morphologic features and performed immunohistochemical staining for markers of Mullerian, Wolffian, mesothelial, and sex cord stromal derivation to explore the relationship between these entities. Histologically, all BTs were benign, microscopic, and incidental. RO was prominent and hyperplastic with gradual or abrupt transition to BT. In addition, focal areas of rete entrapped between BT nests were seen. All BTs were positive for GATA-3 and negative for PAX-8. Conversely, the RO in all cases was negative for GATA-3 and positive for PAX-8. WT-1 was positive in both entities. Sex cord stromal and mesothelial markers (other than WT-1) were negative in BT and RO. Although morphologically, BTs seem to arise from RO in these cases, they have a distinct immunophenotype. It is possible that at least some BTs arise from metaplastic changes in RO epithelium.

Mass-spectrometry-based proteomic correlates of grade and stage reveal pathways and kinases associated with aggressive human cancers.

Proteomic signatures associated with clinical measures of more aggressive cancers could yield molecular clues as to disease drivers. Here, utilizing the Clinical Proteomic Tumor Analysis Consortium (CPTAC) mass-spectrometry-based proteomics datasets, we defined differentially expressed proteins and mRNAs associated with higher grade or higher stage, for each of seven cancer types (breast, colon, lung adenocarcinoma, clear cell renal, ovarian, uterine, and pediatric glioma), representing 794 patients. Widespread differential patterns of total proteins and phosphoproteins involved some common patterns shared between different cancer types. More proteins were associated with higher grade than higher stage. Most proteomic signatures predicted patient survival in independent transcriptomic datasets. The proteomic grade signatures, in particular, involved DNA copy number alterations. Pathways of interest were enriched within the grade-associated proteins across multiple cancer types, including pathways of altered metabolism, Warburg-like effects, and translation factors. Proteomic grade correlations identified protein kinases having functional impact in vitro in uterine endometrial cancer cells, including MAP3K2, MASTL, and TTK. The protein-level grade and stage associations for all proteins profiled-along with corresponding information on phosphorylation, pathways, mRNA expression, and copy alterations-represent a resource for identifying new potential targets. Proteomic analyses are often concordant with corresponding transcriptomic analyses, but with notable exceptions.

Sex Cord Tumor With Annular Tubules-Like Histologic Pattern in Adult Granulosa Cell Tumor: Case Report of a Hitherto Unreported Morphologic Variant.

Adult granulosa cell tumor (AGCT) and sex cord tumor with annular tubules (SCTAT) are distinct sex cord stromal tumors with different molecular signatures. We present a unique case of an incidental ovarian tumor with mixed AGCT and SCTAT morphologic patterns. Due to the unusual co-occurrence, molecular testing was separately performed on both components. Despite minimal overlap in morphology, both the SCTAT and AGCT components were found to have an identical mutation profile, including the prototypical FOXL2 p.C134W mutation characteristic of AGCT. We thus present the first report of AGCT with SCTAT-like pattern.

Association Between Metabolic Syndrome and Endometrial Cancer Survival in a SEER-Medicare Linked Database.

BACKGROUND: Metabolic syndrome has previously been linked to increased risk of endometrial cancer. This study examines the association between metabolic syndrome and cancer-specific survival (CSS) in early stage and locoregionally advanced endometrial cancer. METHODS: The SEER-Medicare linked database was used to identify a cohort of patients with endometrial cancer between 1992 and 2011 who underwent hysterectomy. Patients with incomplete stage or grade information were excluded. Patients were stratified into early stage (stage I to II) or locoregionally advanced (stage III to IVa) disease. Metabolic syndrome status was determined through Medicare claims 1 year before diagnosis. The relationship between metabolic syndrome and CSS was evaluated using univariable and multivariable Cox proportional hazards regression analyses. RESULTS: A total of 10,090 patients with endometrial cancer were identified. The mean age was 75 and the majority (91.5%) were white. At diagnosis, 86.6% of patients were early stage and 13.4% were locoregionally advanced. Sixteen percent of patients had metabolic syndrome. On stage stratified multivariable analysis, race, income quartile, year of diagnosis, histopathology, and adjuvant treatment were associated with CSS in early stage disease. Presence of metabolic syndrome was associated with worse CSS in early stage disease (hazard ratio=1.28, 95% confidence interval: 1.09-1.53); this difference did not exist for locoregionally advanced disease (hazard ratio=1.18, 95% confidence interval: 0.93-1.49). CONCLUSIONS: In elderly early stage endometrial cancer patients, metabolic syndrome is associated with worse CSS. Control of metabolic syndrome through lifestyle and pharmacologic therapies may improve cancer prognosis in this population.

Uterine double-conditional inactivation of Smad2 and Smad3 in mice causes endometrial dysregulation, infertility, and uterine cancer.

SMAD2 and SMAD3 are downstream proteins in the transforming growth factor-ß (TGF ß) signaling pathway that translocate signals from the cell membrane to the nucleus, bind DNA, and control the expression of target genes. While SMAD2/3 have important roles in the ovary, we do not fully understand the roles of SMAD2/3 in the uterus and their implications in the reproductive system. To avoid deleterious effects of global deletion, and given previous data showing redundant function of Smad2 and Smad3, a double-conditional knockout was generated using progesterone receptor-cre (Smad2/3 cKO) mice. Smad2/3 cKO mice were infertile due to endometrial hyperproliferation observed as early as 6 weeks of postnatal life. Endometrial hyperplasia worsened with age, and all Smad2/3 cKO mice ultimately developed bulky endometrioid-type uterine cancers with 100% mortality by 8 months of age. The phenotype was hormone-dependent and could be prevented with removal of the ovaries at 6 weeks of age but not at 12 weeks. Uterine tumor epithelium was associated with decreased expression of steroid biosynthesis genes, increased expression of inflammatory response genes, and abnormal expression of cell cycle checkpoint genes. Our results indicate the crucial role of SMAD2/3 in maintaining normal endometrial function and confirm the hormone-dependent nature of SMAD2/3 in the uterus. The hyperproliferation of the endometrium affected both implantation and maintenance of pregnancy. Our findings generate a mouse model to study the roles of SMAD2/3 in the uterus and serve to provide insight into the mechanism by which the endometrium can escape the plethora of growth regulatory proteins.

High grade squamous intraepithelial lesion on high-risk HPV negative patients: Why we still need the Pap test.

BACKGROUND: Cervical cancer is caused by high-risk human papillomavirus (hrHPV). Though screening Pap test (PT) has reduced cancer mortality by detecting precursor lesions, there is now a move toward replacing screening PT with hrHPV testing. The aims of this study were to determine hrHPV negative rate in high grade squamous intraepithelial lesion (HSIL) PT in high-risk patients and correlate with histopathology; and to review the hrHPV negative HSIL PT. METHOD: LIS was searched (January 2015-June 2016) for HSIL PT results. Patient chart was reviewed for age, hrHPV co-testing result including genotyping (Aptima® ), and histopathology follow-up (f/u) which was compared between hrHPV-positive and hrHPV-negative groups. hrHPV-negative HSIL PT slides were re-evaluated for concordance with original interpretation. Student t test was used for data analysis. RESULTS: There were 230 patients with HSIL PT who had hrHPV co-testing and 199/230 had histopathological f/u. Majority (210/230, 91.3%) were hrHPV positive, and 20 (8.7%) were hrHPV negative. HrHPV negative HSIL was significantly more common in older women (mean age 49.3 years) compared with hrHPV-positive HSIL (mean age 40.7 years) (P = .0015). The most frequently detected genotype was HPV16 (40%). F/u was CIN2/3 in 145/181 (80%) hrHPV-positive HSIL (includes nine squamous cell carcinoma) and 6/16 (37.5%) hrHPV-negative HSIL. CONCLUSION: Although the risk of CIN2/3 and carcinoma was higher in hrHPV-positive patients, possibility of hrHPV-negative dysplastic lesions should be considered in older women as 6 of 16 (37.5%) of these women had CIN2/3 and/or carcinoma which would have been missed without the PT.

Unusual Presentations of Gynecologic Tumors: Primary, Extrauterine, Low-Grade Endometrioid Stromal Sarcoma.

CONTEXT: - Low-grade endometrial stromal sarcomas, when uterine in location, are relatively easy to diagnose because of characteristic morphology and patterns of myometrial invasion. However, when they occur at extrauterine sites, they fall under the broad umbrella of small round blue cell tumors, making diagnosis challenging, especially when they have variant morphologic features and lack the characteristic pattern of invasion. OBJECTIVES: - To provide an insight into the sites of occurrence of low-grade endometrioid stromal sarcomas, the variant morphologic patterns, clues to diagnosis, and the usefulness of immunohistochemistry as an aid to facilitate correct diagnosis. The outcome of these tumors, in comparison with their uterine counterpart, is also discussed. DATA SOURCES: - Existing peer-reviewed literature was reviewed. CONCLUSIONS: - Low-grade endometrioid stromal sarcoma is an uncommon neoplasm that can be misdiagnosed because of its rarity, unusual location, and presence of numerous variant histologic patterns that mimic other tumors. Knowledge of those features; consideration of this tumor in the differential diagnosis of small, round blue cell tumors at any location in a woman; and an appropriate use of immunohistochemistry can help facilitate the diagnosis.

The Role of Routine Peritoneal and Omental Biopsies at Risk-Reducing Salpingo-Oophorectomy.

STUDY OBJECTIVE: To assess the potential role of peritoneal and omental biopsies in women undergoing risk-reducing salpingo-oopherectomy (RRSO) for prophylactic management of hereditary breast/ovarian cancer (HBOC) syndromes. DESIGN: A retrospective observational cohort (Canadian Task Force classification II.1). SETTING: An academic gynecology practice. PATIENTS: All women who underwent RRSO for a high-risk BRCA1/2 mutation or deletion at a single institution between January 2003 and June 2016. INTERVENTIONS: After obtaining institutional review board approval, patient demographics, types of surgical intervention, histopathology reports, and outcomes were abstracted. Bilateral fallopian tubes were histologically evaluated using the "sectioning and extensively examining of the fimbriated end" protocol. Descriptive statistics were used to summarize findings. MEASUREMENTS AND MAIN RESULTS: Seventy women underwent RRSO within the study window; 60% (n = 42) carried a high-risk mutation in BRCA1, 37.1% (n = 26) carried a high-risk mutation in BRCA2, and 2.9% (n = 2) had a high-risk BRCA deletion identified by BRAC analysis rearrangement testing (BART). Serous tubal intraepithelial carcinomas were identified in the distal fallopian tube of 3 subjects. In addition to RRSO, subjects underwent pelvic washings (n = 58, 82.9%), omental biopsy (n = 44, 62.9%), peritoneal biopsies of the bilateral paracolic gutters (n = 51, 72.9%), anterior and posterior cul-de-sac (n = 53, 75.7%), and rectosigmoid mesentery (n = 11, 15.7%). Rare atypical cells favoring reactive cells were identified in pelvic washings of 1 subject (1.7%) with histologically normal fallopian tubes. No evidence of atypical mesothelial proliferations or carcinoma was identified in any omental or peritoneal biopsies. The mean duration of follow-up was 32.5 ± 24.7 months. At the last contact, 3 women (4.3%) had died of metastatic breast cancer, whereas another 3 (4.3%) had been diagnosed with a recurrence of their breast cancer. All other subjects were alive and well (n = 64, 91.4%). CONCLUSION: The routine use of peritoneal and omental biopsies for women undergoing RRSO does not appear to improve detection of occult malignancy.

Prognostic value of endocervical sampling following loop excision of high grade intraepithelial neoplasia.

OBJECTIVE: To assess the role of additional biopsies performed with loop electrosurgical excisional procedure (LEEP) in predicting the likelihood of persistent high grade intraepithelial neoplasia. METHODS: Clinicopathologic data were abstracted from women who underwent excision of high grade intraepithelial lesions between 2001 and 2014. Persistent disease was defined as uninterrupted high grade intraepithelial neoplasia, whereas recurrent disease was defined as disease diagnosed ≥1year after treatment with intervening normal evaluation. Chi-square and Fisher's exact tests were used to examine associations between demographic and histologic parameters and clinical outcomes. RESULTS: A total of 606 women underwent LEEP for high grade intraepithelial neoplasia (HSIL), of whom, 178 (29%) were additionally evaluated by endocervical curettage, 80 (13%), top hat and 99 (16%), both procedures. With mean follow-up of 1.9±1.5years, persistent disease was identified in 87 women (14%) while recurrent disease was diagnosed in 20 (3%). After adjusting for age, HIV status and histologic grade of disease, the presence of disease at the endocervical margin (aOR=2.2, 95% CL 1.8-5.5, p<0.0001), with endocervical curettage (aOR=2.39, 95% CL 1.2-9.9, p=0.025) or on top hat (aOR=4.0, 95% CL 1.1-16.2, p=0.04) correlated with the likelihood of persistent but not recurrent disease. Only endocervical margin status remained predictive (p=0.03) of outcome after controlling for pre-procedure likelihood of endocervical disease. Sensitivity of endocervical margin status for persistent disease was 56.9% with specificity of 72.2%. Positive predictive value (PPV) was 24.9% and negative predictive value (NPV) 90.9%. CONCLUSIONS: Despite frequent use of additional procedures to sample the endocervix, these strategies do not improve the ability of endocervical margin status to predict persistent or recurrent dysplasia.

Molecular Targets and Emerging Therapeutic Options for Uterine Leiomyosarcoma.

Uterine leiomyosarcoma (uLMS) is an aggressive malignancy characterized by its early metastasis, high rates of recurrence, and poor prognosis. Multiple obstacles complicate the clinical management of uLMS. These include the fact that most uLMS are typically identified only after a woman has undergone hysterectomy or myomectomy, the limited efficacy of adjuvant therapy for early stage disease, and the poor response of metastatic disease to current treatments. Here, we discuss recent insights into the molecular basis of uLMS and discuss emerging options for its clinical management. Particular attention is given to the biologic basis of these strategies with the goal of understanding the rationale motivating their use.