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Purpose:Copy number–high endometrial carcinomas were described by The Cancer Genome Atlas as high-grade endometrioid and serous cancers showing frequent copy-number alterations (CNA), low mutational burden (i.e., non-hypermutant), near-universal TP53 mutation, and unfavorable clinical outcomes. We sought to investigate and compare the clinicopathologic and molecular characteristics of non-hypermutant TP53-altered endometrial carcinomas of four histologic types.Experimental Design:TP53-mutated endometrial carcinomas, defined as TP53-mutant tumors lacking microsatellite instability or pathogenic POLE mutations, were identified (n = 238) in a cohort of 1,239 endometrial carcinomas subjected to clinical massively parallel sequencing of 410–468 cancer-related genes. Somatic mutations and CNAs (n = 238), and clinicopathologic features were determined (n = 185, initial treatment planning at our institution).Results:TP53-mutated endometrial carcinomas encompassed uterine serous (n = 102, 55.1%), high-grade endometrial carcinoma with ambiguous features/not otherwise specified (EC-NOS; n = 44, 23.8%), endometrioid carcinomas of all tumor grades (n = 28, 15.1%), and clear cell carcinomas (n = 11, 5.9%). PTEN mutations were significantly more frequent in endometrioid carcinomas, SPOP mutations in clear cell carcinomas, and CCNE1 amplification in serous carcinomas/EC-NOS; however, none of these genomic alterations were exclusive to any given histologic type. ERBB2 amplification was present at similar frequencies across TP53-mutated histologic types (7.7%–18.6%). Although overall survival was similar across histologic types, serous carcinomas presented more frequently at stage IV, had more persistent and/or recurrent disease, and reduced disease-free survival.Conclusions:TP53-mutated endometrial carcinomas display clinical and molecular similarities across histologic subtypes. Our data provide evidence to suggest performance of ERBB2 assessment in all TP53-mutated endometrial carcinomas. Given the distinct clinical features of serous carcinomas, histologic classification continues to be relevant.

Supplementary Methods Supplementary Figures S1-S5 Supplementary Tables S1, S2

Adult granulosa cells tumors (AGCTs) are typically low-grade indolent tumors. On rare occasions, they undergo high-grade/sarcomatous transformation and behave aggressively. This transformation is postulated to occur as the result of acquired genetic alterations, some of which may be eligible for targeted therapy. Here we report a rare case of AGCT with sarcomatous transformation that harbored distinct molecular alterations from those typically seen with AGCTs supporting a molecularly driven approach to these malignancies. The patient is a 56-yr-old G3P3 woman with a history of multiple recurrences of ovarian AGCT for which the first diagnosis was made at the age of 25 when she was evaluated for infertility. The ovarian tumor displayed typical features of AGCT with low-grade, bland morphology. The first extraovarian spread of tumor involving the cul-de-sac was reported at the age of 39. After that, recurrences occurred every 2 to 3 yr with involvement of multiple anatomic sites and repeated surgical resections. At the age of 55 she developed a symptomatic recurrence in the pelvis and underwent resection of an isolated lesion (specimen 1) to no gross residual disease. Within 4 wk of resection she developed significant pelvic pain and imaging showed recurrence of the mass. Therefore, in 5 mo after the initial resection she underwent repeat excision of the lesion (specimen 2) and associated bowel. The sections from specimen 1 showed a biphasic morphology: a low-grade component with morphology and immunophenotype consistent with a typical AGCT and a high-grade spindle cell component with features consistent with a high-grade sarcoma. Specimen 2 featured a pure high-grade sarcoma characterized by coagulative tumor cell necrosis, readily recognizable mitoses, highly atypical cells with vesicular nuclei and prominent nucleoli. SF-1 positivity and the presence of FOXL2 C134W mutation in the sarcomatous component support the notion of transformation of typical AGCT. While detected TERT promoter C228T mutation may play a role in this process, we further identified genetic alterations affecting PI3K/AKT/mTOR pathway, including mutations in PIK3CA , PIK3R1 , AKT1 , and NF2 , which may also contribute to tumor progression/transformation. These findings provide rationale for molecular/pathway-based targeted therapy for patients with advanced AGCT.

Bizarre (atypical/symplastic) cells have been described in various gynecologic normal tissues and benign neoplasms. This type of bizarre cytologic change is usually an incidental finding and is regarded as a benign process. We describe 17 cases of bizarre chorionic-type trophoblast in second-trimester and third-trimester placentas that created concern for an underlying/undersampled or incipient intraplacental trophoblastic neoplasm, predominantly found in intervillous trophoblastic islands (11/17), placental septae (6/17), chorionic plate (1/17), and/or the chorion layer of fetal membranes (2/17). The bizarre trophoblastic cells exhibited sheet-like or nested architecture, had a multifocal/patchy distribution, and/or were present as individual cells within hyaline stroma; they were characterized by large nuclei with smudgy chromatin and occasional intranuclear pseudoinclusions. The degree of atypia was classified as mild (0/17), moderate (3/17), or severe (14/17). Mitotic figures and necrosis were not identified. A dual immunohistochemical stain for trophoblast (hydroxyl-delta-5-steroid dehydrogenase) and a proliferation marker (Ki-67), performed in 15 cases, demonstrated 0% to very low proliferative activity within the bizarre trophoblast (0% to 2% [10/15], 3% to 8% [5/15]). Immunohistochemical stains for fumarate hydratase showed intact/retained expression in the bizarre cells in 7 of 7 cases. Clinical follow-up ranged from 1 to 45 months, and all patients were alive and well without subsequent evidence of a gestational trophoblastic or other neoplasms. We conclude that bizarre chorionic-type trophoblast in second-trimester or third-trimester placentas have the potential to mimic an intraplacental trophoblastic neoplasm but are likely a benign degenerative change. This study expands the spectrum of bizarre cells that occur in the gynecologic tract.

Purpose: Copy number–high endometrial carcinomas were described by The Cancer Genome Atlas as high-grade endometrioid and serous cancers showing frequent copy-number alterations (CNA), low mutational burden (i.e., non-hypermutant), near-universal TP53 mutation, and unfavorable clinical outcomes. We sought to investigate and compare the clinicopathologic and molecular characteristics of non-hypermutant TP53-altered endometrial carcinomas of four histologic types. Experimental Design: TP53-mutated endometrial carcinomas, defined as TP53-mutant tumors lacking microsatellite instability or pathogenic POLE mutations, were identified (n = 238) in a cohort of 1,239 endometrial carcinomas subjected to clinical massively parallel sequencing of 410–468 cancer-related genes. Somatic mutations and CNAs (n = 238), and clinicopathologic features were determined (n = 185, initial treatment planning at our institution). Results: TP53-mutated endometrial carcinomas encompassed uterine serous (n = 102, 55.1%), high-grade endometrial carcinoma with ambiguous features/not otherwise specified (EC-NOS; n = 44, 23.8%), endometrioid carcinomas of all tumor grades (n = 28, 15.1%), and clear cell carcinomas (n = 11, 5.9%). PTEN mutations were significantly more frequent in endometrioid carcinomas, SPOP mutations in clear cell carcinomas, and CCNE1 amplification in serous carcinomas/EC-NOS; however, none of these genomic alterations were exclusive to any given histologic type. ERBB2 amplification was present at similar frequencies across TP53-mutated histologic types (7.7%–18.6%). Although overall survival was similar across histologic types, serous carcinomas presented more frequently at stage IV, had more persistent and/or recurrent disease, and reduced disease-free survival. Conclusions: TP53-mutated endometrial carcinomas display clinical and molecular similarities across histologic subtypes. Our data provide evidence to suggest performance of ERBB2 assessment in all TP53-mutated endometrial carcinomas. Given the distinct clinical features of serous carcinomas, histologic classification continues to be relevant.

ObjectivesHuman papillomavirus (HPV) is known to be associated with squamous intraepithelial lesions (SILs). However, there is limited and conflicting literature on the relationship between bacterial vaginosis (BV) and SIL. The aim of this study is to determine the prevalence of BV and evaluate the association between BV and SIL.MethodsA retrospective study was performed on 10,546 cases between 2012 and 2017. HPV results were available in 7,081 cases.ResultsBV was present in 17.6% of cases. There was significant association between BV, positive HPV infection, and high-grade SIL. BV patients with negative HPV infection showed more squamous abnormalities than BV-negative HPV-negative patients.ConclusionsWe found there is a significant association between BV and SIL. BV is more common among patients with HPV infection and is independently associated with squamous abnormalities in cervical smears and surgical follow-up.

PURPOSE: Copy number-high endometrial carcinomas (ECs) were described by The Cancer Genome Atlas as high-grade endometrioid and serous cancers showing frequent copy number alterations (CNAs), low mutational burden (i.e. non-hypermutant), near universal TP53 mutation and unfavorable clinical outcomes. We sought to investigate and compare the clinicopathologic and molecular characteristics of non-hypermutant TP53-altered ECs of four histologic types. DESIGN: TP53-mutated ECs, defined as TP53-mutant tumors lacking microsatellite instability or pathogenic POLE mutations, were identified (n=238) in a cohort of 1,239 ECs subjected to clinical massively parallel sequencing of 410–468 cancer-related genes. Somatic mutations and CNAs (n=238), and clinicopathologic features were determined (n=185, initial treatment planning at our institution). RESULTS: TP53-mutated ECs encompassed uterine serous (n=102, 55.1%), histologically ambiguous high-grade EC-NOS (n=44, 23.8%), endometrioid carcinomas of all tumor grades (n=28, 15.1%), and clear cell (n=11, 5.9%) carcinomas. PTEN mutations were significantly more frequent in endometrioid carcinomas, SPOP mutations in clear cell carcinomas, and CCNE1 amplification in serous carcinomas/EC-NOS; however, none of these genomic alterations were exclusive to any given histologic type. ERBB2 amplification was present at similar frequencies across TP53-mutated histologic types (7.7%−18.6%). Although overall survival was similar across histologic types, serous carcinomas presented more frequently at stage IV, had more persistent and/or recurrent disease, and reduced disease-free survival. CONCLUSIONS: TP53-mutated ECs display clinical and molecular similarities across histologic subtypes. Our data provide evidence to suggest performance of ERBB2 assessment in all TP53-mutated ECs. Given the distinct clinical features of serous carcinomas, histologic classification continues to be relevant.

Pulmonary artery intimal sarcoma is a rare aggressive intraluminal tumor often misdiagnosed as acute or chronic pulmonary thromboembolism due to its clinical presentation and radiological findings. Thus early diagnosis is very crucial and may improve patient outcome. There is limited literature on diagnosis of pulmonary artery sarcoma by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). Herein, we report a case of mass-like lesion in the PA diagnosed on cytological material obtained by EBUS-TBNA with rapid on-site evaluation (ROSE). The aspirate showed pleomorphic malignant spindled cells arranged in loosely cohesive clusters. The intraluminal origin of PAIS was supported by radiographic findings. Subsequently, the patient received preoperative chemotherapy and underwent tumor resection with reconstruction. This report describes the cytomorphologic features of this rare intravascular tumor and demonstrates how limited cytological sample obtained from EBUS-TBNA with ROSE can be triaged efficiently for ancillary studies like immunohistochemistry and MDM2 amplification, thus expediting the management.

BACKGROUND The cytology diagnosis of glandular cell abnormalities (GCAs) is diagnostically challenging, causing inadequate reproducibility. Histological outcome of GCA on cytology varies from benign to malignant diseases. The goal of this study is to evaluate histological outcome and identify distinctive cohorts of patients with GCA based on human papillomavirus (HPV) status, age, and associated squamous abnormality to stratify the patient into high risk for squamous/glandular lesions. METHODS From 2012 to 2017, out of 162 088 ThinPrep Papanicolaou tests performed, 998 (0.61%) were reported as GCAs. Histologic follow-up was available in 638 cases and 429 had concurrent HPV results. RESULTS The overall rate of high-risk human papillomavirus (hrHPV)-positivity (hrHPV+) was 33.6% (144/429 cases). Among the hrHPV+ cases, 18.1% had cervical intraepithelial neoplasia 2/3 (CIN2/3), 3.5% squamous cell carcinoma (SCC), 3.5% cervical adenocarcinoma in situ (AIS)/adenocarcinoma (ADC), and 2.8% endometrial carcinoma. Among hrHPV- cases, 1.4% had CIN2/3, 1.1% AIS/ADC, and 17.5% endometrial carcinoma. The high-grade cervical lesions (CIN2/3/AIS/ADC) were significantly higher in women with hrHPV+ and associated squamous abnormalities compared to hrHPV- and no squamous abnormality in all age groups except patients >65 years. Endometrial carcinoma was most commonly present in women >65 years especially with HPV- and no associated squamous abnormalities. CONCLUSIONS HPV testing is useful for predicting the risk of high-grade cervical neoplasia in women with GCA especially with associated squamous abnormalities on cytology. The endometrial carcinoma is more frequent in hrHPV- older women. The combination of cytology with knowledge of associated squamous abnormality, hrHPV status, and age can significantly aid in stratifying the patient into high risk for glandular/squamous lesions which facilitates appropriate management of these patients.

Background The prevalence of trichomonas vaginalis (TV) infection is low in developed countries and may be due to its incidental diagnosis and treatment during routine screening. Many countries are adopting a new model based on testing for high-risk (HR) human papillomavirus (HPV) instead of cytology. HPV is known to be associated with squamous intraepithelial lesions (SIL). There is limited and conflicting literature on the relationship between TV and SIL. The aim of this study is to determine the prevalence of TV in different age groups and evaluate the association between TV with SIL, BV (bacterial vaginosis), and HPV infection. Design Retrospective study for cytological histologic correlation was performed on 10,546 cases dated between January 2012 and December 2017. HPV results were available in 7,081 cases. Results The age range was 15 to 84 with a mean of 49 years; 249 patients were TV positive (2.3%). The prevalence was highest in 30 to 65 age group (71.5%). HPV was present in 4,386/7,081 cases (61.9%). The associated between TV and HPV infection was not significant (P < .07). There was a significant association between TV and BV infection (P < .001). In total, 4,649/10,546 patients showed squamous abnormalities (44%), of which 52.6% were TV positive and 43.9% were TV negative. CIN2-3/SCC was significantly greater in TV-positive versus TV-negative patients (P < .007). HPV-positive patients that were TV positive showed more squamous abnormalities than those that were TV negative (P < .043). TV-positive patients with ASCH showed higher grade lesions (CIN2-3/SCC) on follow-up than TV-negative patients (P < .003). Conclusion TV is more common among patients with BV and HPV infection and significantly associated with squamous abnormalities. HPV and ASCH patients with TV showed significant squamous abnormalities. Although TV can be detected incidentally through cytology-based cervical screening, a transition to HPV testing is likely to result in increasing TV prevalence over time.

Several studies suggest that resistance to progesterone may contribute to the pathophysiology of endometriosis. Progesterone mediates its biological activity via the 2 progesterone receptor (PR) isoforms (PR-A and PR-B). Effects of progesterone are determined by the PR-A:PR-B ratio such that a PR-B-dominant state promotes progesterone signaling, whereas a PR-A-dominant state decreases progesterone responsiveness. Our objective was to compare the abundance and cellular localization of the PR isoforms in endometrium and endometriotic lesions from women with and without peritoneal and ovarian endometriosis.This in vitro study was conducted in a tertiary care facility. Reproductive-age women with surgically diagnosed endometriosis (n = 18) and asymptomatic control individuals (n = 20) were prospectively recruited at the late proliferative and the early secretory phases. At laparoscopy, samples of eutopic endometrium, peritoneal and ovarian endometriosis, and disease-free peritoneum were obtained for subsequent immunohistochemical and immunoblot analysis of PR-B and total PR localization and PR-A and PR-B abundance, respectively.The PR-A and PR-B were detected in eutopic endometrium and in peritoneal and ovarian endometriosis but not in disease-free peritoneum from patients with and without endometriosis. In peritoneal endometriosis, PR-A was the predominant isoform detected, whereas both receptors were detected in ovarian endometriosis and eutopic endometrium. In eutopic endometrium, levels of PR-A were significantly elevated in women with endometriosis compared with women without disease, regardless of menstrual phase. The PR-A levels were significantly elevated in ovarian endometriosis compared with peritoneal endometriosis.Endometriotic lesions and eutopic endometrium from women with endometriosis are uniform in a PR-A-dominant state. The data suggest that menstrual efflux of a PR-A-dominant endometrial tissue into the peritoneal cavity may play a role in the pathophysiology of endometriosis.

We reported at the Keynote Forum of Immunology Summit-2015 that recombinant human (rh) TNF-α or rhIL-6 stimulated production of matrix metalloproteinase-9 (MMP-9) in the T/C28a2 and C-28/I2 human immortalized chondrocyte cell lines. Furthermore, we reported that tocilizumab (TCZ), a fully humanized monoclonal antibody which neutralizes IL-6-mediated signaling, inhibited the rhIL-6-mediated increase in the production of MMP-9. IL-6 is also a known activator of the JAK/STAT signaling pathway. In that regard, we evaluated the effect of rhIL-6 on total and phosphorylated Signal Transducer and Activator of Transcription by these chondrocyte lines which showed that whereas STAT3 was constitutively phosphorylated in T/C28a2 chondrocytes, rhIL-6 activated STAT3 in C-28/I2 chondrocytes. The finding that rhIL-6 increased the production of MMP-9 by human immortalized chondrocyte cell lines may have important implications with respect to the destruction of articular cartilage in rheumatoid arthritis and osteoarthritis. Thus, the markedly elevated level of IL-6 in rheumatoid arthritis and osteoarthritis sera and synovial fluid would be expected to generate significant MMP-9 to cause the degradation of articular cartilage extracellular matrix proteins. The finding that TCZ suppressed rhIL-6-mediated MMP-9 production suggests that TCZ, currently employed in the medical therapy of rheumatoid arthritis, could be considered as a drug for osteoarthritis.

Two immortalized human juvenile chondrocyte cell lines, T/C28a2 and C28/I2, were employed to determine the extent to which recombinant human (rh) IL-6 or rh-TNF-α increased the production of matrix metalloproteinase-9 (MMP-9). The effect of rhIL-6 on neutrophil gelatinase-associated lipocalin (NGAL) was also assessed. Although C28/I2 chondrocytes incubated with rhIL-6 (50 ng/ml) increased MMP-9 production which could not be mimicked by the T/C28a2 chondrocyte line, the effect of rhTNF-α on MMP-9 was more robust than with rhIL-6. The combinations of rhIL-6 and soluble IL-6 receptor-α (sIL-6Rα) or rhIL-6 and tocilizumab (TCZ), a fully-humanized recombinant monoclonal antibody that neutralizes the interaction between IL-6 and IL-6R significantly reduced MMP-9 production by C28/I2 chondrocytes. However, TCZ had no effect on rhTNF-α-induced MMP-9 production. By contrast, rhIL-6 did not increase the production of NGAL by C28/I2 chondrocytes although the number of NGAL-positive cells was significantly reduced by sIL-6R compared to its control group, but not by the combination of rhIL-6 plus TCZ compared to rhIL-6. In summary, these results showed that rhIL-6 stimulated the production of MMP-9, but not NGAL, in the C28/I2 chondrocyte line. TCZ or sIL-6Rα suppressed rhIL-6-induced MMP-9 production.

Progesterone is a key hormonal regulator of the female reproductive system. It plays a major role to prepare the uterus for implantation and in the establishment and maintenance of pregnancy. Actions of progesterone on the uterine tissues (endometrium, myometrium and cervix) are mediated by the combined effects of two progesterone receptor (PR) isoforms, designated PR-A and PR-B. Both receptors function primarily as ligand-activated transcription factors. Progesterone action on the uterine tissues is qualitatively and quantitatively determined by the relative levels and transcriptional activities of PR-A and PR-B. The transcriptional activity of the PR isoforms is affected by specific transcriptional coregulators and by PR post-translational modifications that affect gene promoter targeting. In this context, appropriate temporal and cell-specific expression and function of PR-A and PR-B are critical for normal uterine function.Relevant studies describing the role of PRs in uterine physiology and pathology (endometriosis, uterine leiomyoma, endometrial cancer, cervical cancer and recurrent pregnancy loss) were comprehensively searched using PubMed, Cochrane Library, Web of Science, and Google Scholar and critically reviewed.Progesterone, acting through PR-A and PR-B, regulates the development and function of the endometrium and induces changes in cells essential for implantation and the establishment and maintenance of pregnancy. During pregnancy, progesterone via the PRs promotes myometrial relaxation and cervical closure. Withdrawal of PR-mediated progesterone signaling triggers menstruation and parturition. PR-mediated progesterone signaling is anti-mitogenic in endometrial epithelial cells, and as such, mitigates the tropic effects of estrogen on eutopic normal endometrium, and on ectopic implants in endometriosis. Similarly, ligand-activated PRs function as tumor suppressors in endometrial cancer cells through inhibition of key cellular signaling pathways required for growth. In contrast, progesterone via PR activation appears to increase leiomyoma growth. The exact role of PRs in cervical cancer is unclear. PRs regulate implantation and therefore aberrant PR function may be implicated in recurrent pregnancy loss (RPL). PRs likely regulate key immunogenic factors involved in RPL. However, the exact role of PRs in the pathophysiology of RPL and the use of progesterone for therapeutic benefit remains uncertain.PRs are key mediators of progesterone action in uterine tissues and are essential for normal uterine function. Aberrant PR function (due to abnormal expression and/or function) is a major cause of uterine pathophysiology. Further investigation of the underlying mechanisms of PR isoform action in the uterus is required, as this knowledge will afford the opportunity to create progestin/PR-based therapeutics to treat various uterine pathologies.