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Low-grade endometrial stromal sarcoma (ESS) is a hormone-responsive low-grade sarcoma typically occurring in the uterine corpus in women. Their genetic hallmarks are recurrent gene fusions involving JAZF1, partnering with either SUZ12 gene or less commonly with PHF1. Low-grade ESS-like sarcoma, or endometrioid stromal sarcoma, is exceptionally rare in males, and has been reported to date only in two cases, one in the paratesticular area and the other of prostatic stromal origin. We report herein two new cases of low-grade ESS-like sarcoma in male patients, one presenting as a periprostatic/peri-rectal mass with a JAZF1-GLI3 fusion, while the other as a paratesticular mass with a JAZF1-PHF1 fusion. As the GLI3 fusion appeared novel, we searched the transcriptional signature of 35 low-grade ESS from our archives, and found a similar JAZF1-GLI3 fusion in a low-grade ESS arising from the uterine corpus, supporting a common pathogenesis. Histopathologically, both cases demonstrate cellular, monotonous proliferation of ovoid to fusiform cells with a background of arteriolar vascular network. Immunohistochemically, the neoplastic cells express ER, PR, and CD10, similar to ESS. One case also expresses diffuse and strong AR. On follow-up, the patient with the periprostatic mass recurred two years after initial surgery with peritoneal 'sarcomatosis'. We describe the salient diagnostic morphologic, immunohistochemical and molecular features, and discuss the differential diagnosis and possible pathogenesis of this unusual entity. This article is protected by copyright. All rights reserved.

Intravascular tumor thrombus (ITT) is a dangerous condition defined as tumor extension into a blood vessel. Endometrial stroma sarcomas (ESS) rarely involve the great vessels [1]. ESS are rare, indolent tumors that account for 25% of uterine sarcomas [2], and they are usually classified as low-grade (LG) or high-grade (HG) [3]. Whilst 29 LG-ESS cases of ITT have been described in the literature since 1986 (Table 1), no cases of ITT from HG-ESS have been reported yet. The present study reports the case of a 57-year-old patient with a recurrence of HG-ESS. Five years before presenting at our institution, the patient underwent total abdominal hysterectomy with bilateral adnexectomy and systematic pelvic lymphadenectomy, followed by chemo-radiotherapy for HG-ESS (FIGO stage III C) [4]. During routine follow-up, a computed tomography (CT) scan diagnosed a recurrence of HG-ESS at the para-caval lymph nodes.

Objective This review aims to analyze the pathological aspects, diagnosis and treatment of rare mesenchymal uterine tumors. Methods On August 2019, a systematic review of the literature was done on Pubmed, MEDLINE, Scopus, and Google Scholar search engines. The systematic review was carried out in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes statement (PRISMA). The following words and key phrases have been searched: "endometrial stromal sarcoma", "low-grade endometrial stromal sarcoma", "high-grade endometrial stromal sarcoma", "uterine sarcoma", "mesenchymal uterine tumors" and "uterine stromal sarcoma". Across these platforms and research studies, five main aspects were analyzed: the biological characteristics of the neoplasms, the number of cases, the different therapeutic approaches used, the follow-up and the oncological outcomes. Results Of the 94 studies initially identified, 55 were chosen selecting articles focusing on endometrial stromal sarcoma. Of these fifty-five studies, 46 were retrospective in design, 7 were reviews and 2 randomized phases III trials. Conclusion Endometrial stromal sarcomas are rare mesenchymal uterine neoplasms and surgery represents the standard treatment. For uterus-limited disease, the remove en bloc with an intact resection of the tumor (without the use of morcellation) is strongly recommended. For advanced-stage disease, the standard surgical treatment is adequate cytoreduction with metastatectomy. Pelvic and para-aortic lymphadenectomy is not recommended in patients with Low-grade Endometrial Stromal Sarcoma (ESS), while is not clear whether cytoreduction of advanced tumors improves patient survival in High-grade ESS. Administration of adjuvant radiotherapy or chemotherapy is not routinely used and its role is still debated.

Recently a novel subtype of endometrial stromal sarcoma (ESS) defined by recurrent genomic alterations involving BCOR has been described (HGESS‐BCOR). We identified a case of HGESS‐BCOR with a ZC3H7B‐BCOR gene fusion, which harbored an amplification of the MDM2 locus. This index case prompted us to investigate MDM2 amplification in four additional cases of HGESS‐BCOR. Tumors were analyzed for MDM2 amplification by array‐based profiling of copy number alterations (CNAs) and fluorescence in situ hybridization (FISH), as well as for MDM2 expression by immunohistochemistry (IHC). Additionally, a cohort of other mesenchymal uterine neoplasms, including 17 low‐grade ESS, 6 classical high‐grade ESS with YWHAE‐rearrangement, 16 uterine tumors resembling ovarian sex cord tumors, 7 uterine leiomyomas and 8 uterine leiomyosarcomas, was analyzed for CNAs in MDM2. Copy number profiling identified amplification of the 12q15 region involving the MDM2 locus in all five HGESS‐BCOR. Subsequent validation analyses of three tumors confirmed MDM2 amplification using MDM2 FISH. Accordingly, IHC showed MDM2 overexpression in all analyzed cases. None of the other uterine neoplasms in our series, including tumors that are in the histopathological differential diagnoses of HGESS‐BCOR, showed copy number gains of MDM2. Together, our results indicate that HGESS‐BCOR carries MDM2 amplifications, which has diagnostic implications and could potentially be used for targeted therapies in these clinically aggressive tumors.

金沢大学医薬保健研究域医学系, Endometrial stromal nodule (ESN) and low-grade endometrial stromal sarcoma (LG-ESS) are rare uterine tumors known as endometrial stromal tumors (ESTs). In addition to their similarity in morphological features, recent studies have shown that these two tumors share common genetic alterations. In particular, JAZF1-SUZ12 fusion is found with high frequency in both ESN and LG-ESS. In LG-ESS, some minor fusions have also been described, which include rearrangements involving PHF1 and its partner genes, such as JAZF1, EPC1, MEAF6, BRD8, EPC2, and MBTD1. Because of the rarity of ESN, genetic alterations other than JAZF1 fusion have not been investigated in detail. In this study, we performed a next-generation sequencing-based analysis in a case of ESN with peripheral metaplastic bone formation and detected MEAF6-PHF1 fusion, which has been reported in a small subset of uterine LG-ESSs and soft tissue ossifying fibromyxoid tumors. The finding that MEAF6-PHF1 fusion is a background genetic abnormality detected both in ESN and LG-ESS, along with JAZF1-SUZ12, provides further support for the similarity and continuum between these two types of ESTs. Furthermore, the association between metaplastic bone formation and MEAF6-PHF1 fusion may not be limited to soft tissue tumors. © 2020 Wiley Periodicals LLC

The classification of endometrial stromal sarcoma (ESS) has been refined and aided by the discovery of various recurrent gene translocations. Low-grade ESS (LG-ESS) is most commonly characterized by JAZF1-SUZ12 fusions followed by rearrangements involving PHD finger protein-1 (PHF1) and multiple fusion partners, including JAZF1, EPC1, EPC2, and MEAF6. In the present study, integrating anchored polymerase chain reaction and paired-end next-generation ribonucleic acid sequencing, we identified the presence of a novel malignant brain tumor domain-containing 1 (MBTD1)-PHF1 gene fusion in a case of LG-ESS. MBTD1 belongs to the Polycomb gene group, and its fusion with PHF1 is predicted to mediate tumorigenesis through aberrant transcriptional repression. Histology and immunohistochemical studies demonstrated conventional morphology for LG-ESS and clinical follow-up showed no progression of disease after 6 months. These findings help expand the current knowledge on the spectrum of gene rearrangements in the diagnosis of ESS.

Uterine sarcomas (USs) are a group of rare but aggressive uterine malignancies, accounting for only 1% of the malignant tumors of female reproductive organs. Due to the high rate of recurrence and metastasis, the prognosis of USs is poor. Given the high mortality rate and limited clinical benefit of surgery and adjuvant chemoradiotherapy, hormonal therapy has shown good prospects in recent years. Hormonal agents include progestins, aromatase inhibitors (AIs), and gonadotropin‐releasing hormone analogue (GnRH‐a). According to the literature, hormonal therapy has been confirmed effective for recurrent, metastatic or unresectable low‐grade endometrial stromal sarcoma (LGESS) and hormone receptor positive (ER+/PR+) uterine leiomyosarcoma (uLMS) with favorable tolerance and compliance. Besides, hormonal therapy can also be used in patients with early‐staged disease who desire to preserve fertility. However, due to the rarity of USs, the rationale of hormonal therapy is generally extrapolated from data of hormone‐sensitive breast cancer, and present studies of hormonal therapy in USs were almost limited to case reports and small‐sized retrospective studies. Therefore, further systematic researches and standardized clinical trials are needed to establish the optimal hormonal therapy regimen of USs. Herein, we reviewed the existing studies related to the hormonal therapy in USs in order to provide reference for clinical management in specific settings.

Low-grade endometrial stromal sarcoma (LGESS) is a rare malignant uterine tumor with the potential to metastasize years after the primary resection. There is a broad differential diagnosis for endometrial stromal sarcomas (ESS), including both benign and malignant entities. Herein, we present the case of a 64-year-old female with metastatic LGESS to the lung, diagnosed by cytology, 24 years after her initial presentation. This report discusses the cytomorphologic and histopathologic characteristics, and ancillary studies including immunohistochemical stains and recent advances in molecular diagnostics of ESS. Accurate diagnosis of spindle cell lesions in the lung can be challenging. As such, this case highlights the instrumental role of ancillary testing and molecular diagnostics to achieve a more definitive diagnosis.

Endometrial stromal sarcoma encompasses a heterogeneous group of uterine mesenchymal neoplasms, which are currently divided into low-grade and high-grade subtypes. Low-grade endometrial stromal sarcoma is morphologically bland; molecularly, these tumors frequently contain JAZF1-SUZ12, JAZF1-PHF1, and EPC1-PHF1 fusions. In contrast, high-grade endometrial stromal sarcoma is characterized by morphologically undifferentiated neoplasms with high-grade nuclear features; these tumors likewise appear to be genetically diverse with YWHAE-NUTM2 and ZC3H7B-BCOR representing the most frequent gene fusions. Herein, we describe two novel EPC1 fusion genes in endometrial stromal sarcoma: EPC1-SUZ12 and EPC1-BCOR. Both tumors were characterized be an aggressive clinical course.

Aim To investigate the effects of leuprorelin using a self-administered quality-of-life (QOL) questionnaire in patients with recurrent gynecological cancer. Methods Records of patients who received 3.75 mg leuprorelin every 4 weeks for the treatment of recurrent gynecological cancer were retrospectively reviewed. The physical domain of the QOL questionnaire, Care Notebook, was used to assess physical symptoms. Symptom deterioration was defined as a ≥10-point increase in baseline score; otherwise, symptoms were defined as controlled. Radiological and serological responses were evaluated according to the 2011 Gynecological Cancer Intergroup criteria. Results From 2007 to 2015, 25 patients were administered leuprorelin for the treatment of epithelial ovarian cancer, granulosa cell tumor, endometrial cancer, endometrial stromal sarcoma and clear cell cervical cancer (in 13, 3, 6, 2 and 1 patients, respectively). Twenty patients had received a median of three lines (range 1-12 lines) of chemotherapy. Ten patients had progressive disease during their previous round of chemotherapy. Twenty patients completed the questionnaire every 4 weeks. Following leuprorelin treatment for 8 weeks, the symptom and disease control rates were 65% (13/20) and 44% (11/25), respectively. Two patients, one each with granulosa cell tumor and endometrial cancer, had stable disease at 6 months. Among the 20 patients who completed the QOL questionnaire, symptom control and disease control at 8 weeks showed a significant correlation (P = 0.016). Conclusion Leuprorelin had minimal anticancer activity. The physical domain of the QOL questionnaire could be used to assess effects of hormonal treatment.

Considering the characteristics of low-grade endometrial stromal sarcoma (ESS), such as relative indolent course, younger age at diagnosis and favorable prognosis, the fertility-preserving management of low-grade ESS has been described by several authors. We report a 34-year-old female with stage IB low-grade ESS who developed recurrence 7 years after neoadjuvant high-dose progestin therapy followed by fertility-preserving surgery and postoperative progestin therapy. The patient stopped progestin therapy and was disease free for 4 years after diagnosis but experienced recurrence with peritoneal dissemination at 7 years. Considering the tendency of late recurrence, long-term surveillance is necessary to ensure timely action. Long-term progestin treatment might be considered after complete remission even beyond 5 years. We performed a literature review and found that many of the cases did not meet solid pathological criteria of low-grade ESS. The diagnostic criteria of low-grade ESS (vs endometrial stromal nodule) should be deliberately documented for future studies of this rare disease.

Uterine leiomyosarcoma (u-LMS) and endometrial stromal sarcoma (ESS) are among the most frequent soft tissue sarcomas, which, in adults, lead to fatal lung metastases and patients have an extremely poor prognosis. Due to their rarity and heterogeneity, there are no suitable biomarkers for diagnosis and prognosis, although some biomarker candidates have appeared. In 2017, The Cancer Genome Atlas (TCGA) Research Network's work on u-LMS has confirmed mutations and deletions in RB1, TP53 and PTEN. In addition, whole-exome sequencing of u-LMS has confirmed and demonstrated frequent alterations in TP53, RB1, α-thalassemia/mental retardation syndrome X-linked (ATRX) and mediator complex subunit 12 (MED12). MED12 is a useful biomarker to diagnose uterine-derived LMS and tumors arising from (LM) with a relatively favorable prognosis. TP53 and ATRX mutations can be important mechanisms in the pathogenesis of u-LMS and are correlated with a poor prognosis. In an update based on the 2014 WHO classification, low-grade ESS is often associated with gene rearrangement bringing about the JAZF 1-SUZ12 (formerly JAZF1-JJAZ1) fusion gene, whereas high-grade ESS is associated with the YWHAE-NUTM fusion gene. Low-grade ESS with JAZF1 rearrangement may correlate with metastasis. However, high-grade ESS with metastasis with YWHAE rearrangement shows a relatively favorable prognosis. The genetic/molecular genetic aberrations in u-LMS and ESS are reviewed, focusing on molecular biomarkers for these primary and metastatic tumors.

Objective To determine the prevalence of occult pre-malignant or malignant uterine pathology at the time of laparoscopic surgery with open power morcellation for benign gynecologic disease. Methods The present multicenter, retrospective cohort study included women who underwent open power morcellation for benign indications between January 1, 2007, and February 28, 2014, at three academic medical centers in the USA. The primary outcome was pre-malignant or malignant pathology at the time of open power morcellation, and was determined from the patients' pathology reports. Results During the study period, 1214 women underwent open power morcellation for benign indications. Similar preoperative characteristics were observed between patients with normal pathology and those with pre-malignant or malignant uterine pathology, including body mass index, parity, hypertension, diabetes, breast cancer, and smoking (all P>0.129). Among patients who underwent open power morcellation, 14 (1.2%) had occult pre-malignant or malignant pathology; 5 (0.4%) women had endometrial adenocarcinoma and 1 (0.1%) had low-grade endometrial stromal sarcoma. There were eight patients with malignant pathology who underwent additional surgical exploration and were disease free at their final clinical visit, with a median follow-up time of 42.0 months (interquartile range 5.0-62.0 months). Conclusion Endometrial adenocarcinoma and low-grade endometrial stromal sarcoma were rare in the present study and there were no reports of leiomyosarcoma.

Aims MED12 exon 2 mutations have been identified in most uterine leiomyomas and mammary fibroepithelial tumours. MED12 has not been genotyped in most other gynaecological mesenchymal tumours. The purpose of this study was to determine the prevalence of MED12 mutations in uncommon gynaecological mesenchymal tumours. Methods and results Sixty-eight uncommon gynaecological mesenchymal tumours were genotyped for MED12 exon 2, including 27 Mullerian adenosarcomas (including three tentatively diagnosed as ‘variant adenosarcomas’), six cellular angiofibromas, six aggressive angiomyxomas, five angiomyofibroblastomas, five superficial myofibroblastomas, five atypical polypoid adenomyomas, and 14 endometrial stromal sarcomas. Immunohistochemistry for CD10, myogenic markers, hormone receptors, MDM2, and CDK4, and fluorescence in-situ hybridization (FISH) for JAZF1, PHF1 and YWHAE rearrangement, were performed on selected cases. The three ‘variant adenosarcomas’ harboured MED12 exon 2 mutations (including p.L36R hotspot mutation, recurrent p.L39_A50del, and a novel splice site mutation). Three endometrial stromal sarcomas with JAZF1–SUZ12 or JAZF1–PHF1 fusion harboured unprecedented mutations (p.D54G in two, and p.Q48* in one). All remaining tumours were wild-type. The three MED12-mutated ‘variant adenosarcomas’ showed distinctive morphological features, including ‘fibromyomatous’ cytomorphology, a close association with adenomyosis, clustered thick-walled vessels, focal conspicuous hyalinization, and intralymphovascular tumour growth. Features of conventional adenosarcomas, including nuclear atypia, mitotic activity, periglandular condensation, and phyllodes-like architecture, were inconspicuous. All three cases showed immunoreactivity for desmin and hormone receptors, while being negative for MDM2 and CDK4; they showed no JAZF1, PHF1 or YWHAE rearrangement. Despite deep myoinvasion, these tumours followed an indolent clinical course. Conclusions These MED12-mutated adenosarcoma-like tumours might represent a distinct entity that requires more studies for its identification. MED12 exon 2 mutations seemed to have no significant role in other uncommon gynaecological mesenchymal tumours.

Aim The study was conducted to delineate the histological problems in diagnosing uterine mesenchymal tumors in morcellated material. Methods All cases of morcellated uteri performed between 2008 and 2014 were reviewed. The incidence of unexpected malignancy, defined as any neoplasm with a clear-cut diagnosis of leiomyosarcoma (LMS) or endometrial stromal sarcoma (ESS), was noted. Cases with absolute discrepancy between the diagnosis of the morcellated tumor and the subsequent diagnosis were also included in the study. Results Out of 631 cases, a final diagnosis of LMS or ESS was made regarding three and five tumors, respectively. Patient age ranged from 25 to 48 years. Two further cases initially diagnosed as ESS proved to be endometrial stromal nodules with smooth muscle differentiation. Two cases were diagnosed as smooth muscle tumors with uncertain malignant potential and the patients remain free of disease. One tumor was diagnosed as an endometrial stromal neoplasm and proved to be benign and finally a leiomyoma variant presented with presumed peritoneal disease. Conclusion Both endometrial stromal and smooth muscle tumors with malignant behavior can be encountered at a young age. Because of the limitations in histological evaluation, morcellated tumors may be overdiagnosed or underdiagnosed by pathologists.

Aim A nomogram for prediction of 12-year sarcoma-specific survival has been developed based on patients with soft tissue sarcomas treated in Memorial Sloan Kettering Cancer Centre (MSKCC). We aim to evaluate the predictive accuracy of the MSKCC sarcoma nomogram in a cohort of patients treated at an Asian institution. This has not been validated in an Asian population and thus its universal applicability remains unproven. Materials and methods Between 1990 and 2013, 840 adult patients underwent treatment for primary soft tissue sarcoma (STS) at the National Cancer Centre Singapore. Patients who presented with locally recurrent or metastatic disease were excluded from the analysis. The variables included in the MSKCC nomogram included age at diagnosis, tumor size, histologic grade, histologic subtype, depth and site. A total of 399 patients were left for analysis. The nomogram was validated by assessing its extent of discrimination and level of calibration. Results All patients had deep tumors. Disease occurred most commonly in the lower extremity (n = 149 [37.3%]), the most common histologic subtype was “Others” (angiosarcoma, ewing's sarcoma, endometrial stromal sarcoma, sarcoma NOS [not otherwise specified] and rhabdomyosarcoma). Sixty-four percent of all patients had high-grade tumors while 36% had low-grade tumors. The median patient age at diagnosis was 54 years (range: 17–88 years). The median follow up time for all patients and surviving patients were 29 (range: 1–174) and 33 (range: 1–157) months, respectively. The observed 5- and 10-year sarcoma-specific survival were 55% and 33%, respectively. The concordance index was 0.71. For level of calibration, the observed correspondence between predicted and actual outcomes suggest that the MSKCC nomogram generally predicts well for patients with higher survival probability, but consistently overpredicts survival for the other groups, in our cohort of patients. Conclusion The MSKCC sarcoma nomogram was found to be accurate in terms of extent of discrimination. In terms of level of calibration, it generally predicts well for patients with higher survival probability, but consistently overpredicts survival for the other groups in our population.

Recent cytogenetic and molecular investigations have improved our understanding of endometrial stromal tumors, including sarcomas (ESS), and helped redefine their classification into more pathogenetically meaningful categories. Because much more can be gained through such studies, we add information on another 22 ESS examined by karyotyping, PCR analysis, expression array analysis, and transcriptome sequencing. In spite of the known preference for certain pathogenetic pathways, we found considerable genetic heterogeneity in high‐grade (HG) as well as in low‐grade (LG) ESS. Not all HG tumors showed a YWHAE‐NUTM chimeric transcript and as many as six LGESS showed no hitherto known ESS‐related fusions. Among the transcripts identified by transcriptome sequencing and verified by Sanger sequencing, new variants of ZC3H7‐BCOR and its reciprocal BCOR‐ZC3H7 were identified as was involvement of the CREBBP and MLLT4 genes (both well known leukemia‐related genes) in two new fusions. FISH analysis identified a known EPC1‐PHF1 fusion which led to the identification of a new variant at the molecular level. The fact that around 70 genes were found differentially expressed, by microarray analysis, when comparing LGESS showing ESS‐related fusions with LGESS without such transcripts, underscores the biochemical importance of the observed genetic heterogeneity and hints that new subgroups/entities in LGESS still remain undiscovered. © 2016 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.

Pulmonary tumor thromboembolus (PTTE) secondary to uterine cancer is a rare cause of sudden unexpected deaths in the elderly population. Additionally, tumor extension to the inferior vena cava (IVC) makes it rarer. No such cases have been previously reported in the forensic literature. We report this phenomenon in a previously healthy 70-year-old woman with no other known risk factors for the development of deep vein thrombosis. The deceased was found dead while watching television with her relatives. Autopsy examination revealed that her death was attributed to a saddle embolus lodged in the main pulmonary arteries. A uterine tumor was discovered, and microscopic examination revealed low-grade endometrial stromal sarcoma with angiolymphatic invasion. The tumor cells were also found in the embolus and the remnant thrombosis attached to the inner wall of the IVC. This case demonstrates a sudden unexpected death caused by acute PTTE following seeding of uterine cancer into the IVC and raises awareness of such events.

Aim The aim of this study was to identify the preoperative diagnostic findings suggestive of uterine sarcoma. Methods We retrospectively reviewed the medical records of 31 patients with pathologically confirmed uterine sarcoma including leiomyosarcoma, endometrial stromal sarcoma, and undifferentiated sarcoma, between 2003 and 2011. The cases were matched by age, year of procedure (plus or minus 1 year), and surgeon, to controls (1:3 ratio) selected from all the patients who underwent hysterectomy for uterine myoma during the same period. Results Uterine sarcomas had larger tumor size compared with leiomyoma on sonography (P = 0.006). There was no significant difference in the total number of masses found on ultrasonography (P = 0.066). On multivariate analysis increased neutrophil-to-lymphocyte ratio (NLR > 2.1), large tumor size (> 8.0 cm), and lower body mass index (BMI ≤ 20) were independent risk factors for uterine sarcoma (P = 0.014, 0.048, and 0.048, respectively). Sarcoma index was calculated by summing the number of risk factors. Higher sarcoma index was associated with increased risk of uterine sarcoma (0, 13.6%; 1, 21.7%; 2, 62.5%; 3, 100%). Conclusion Preoperative NLR, tumor size, and BMI could be useful for the discrimination of sarcoma from leiomyoma of uterus.

Endometrial stromal nodules are rare benign tumors that appear as well-circumscribed globular masses in the myometrium. In this report, a myometrial mass exhibited heterogeneous hyperintensity without hypointense bands on T2-weighted images and homogeneous isointensity on T1-weighted images. A dynamic contrast study revealed the same degree of uterine myometrial enhancement only in the marginal area. The structures were pathologically confirmed to correspond with proliferating endometrial stromal cells. Herein, we report this rare tumor and the correlation between magnetic resonance imaging and pathological findings.

High grade endometrial stromal sarcoma (HGESS) is an uncommon malignancy recently re-defined in the new WHO classification of endometrial stromal tumors. In this article, we discuss the differential diagnoses of metastatic HGESS in a fine needle aspiration (FNA) of a lymph node and compare the cytomorphology of HGESS in ThinPrep [(TP), Hologic Inc., Boxborough, MA] to conventional smears (CS). The patient had a history of stage I HGESS, status-post supracervical hysterectomy without regional lymph node metastases. Her post-operative course was complicated by pelvic fluid collections and enlarging para-aortic lymph nodes. Diff-Quik (DQ)-stained and Papanicolaou (Pap)-stained smears from a para-aortic lymph node FNA demonstrated a cellular specimen with monomorphic population of plump to oval cells with scant, wispy cytoplasm in aggregates and as single cells. The nuclei showed fine chromatin and small inconspicuous nucleoli. Compared to the CS, HGESS cells in the TP showed similar cytological features, with the exception that the nuclei were slightly smaller, hyperchromatic, and the chromatin pattern was attenuated. In the absence of prior clinical history, the cytomorphology of metastatic HGESS in a lymph node can be difficult to differentiate from a lymphoma, a variety of metastatic spindle cell tumors or metastatic carcinoma. Immunohistochemical analysis and comparison with the primary tumor can be useful in proving the nature of the malignant cells. The cytomorphology of HGESS on TP correlated well in both single cells and aggregates when compared to CS. The differences noted were decreased nuclear size, nuclear hyperchromasia, and slightly attenuated nuclear detail on TP. Diagn. Cytopathol. 2015;43:756–762. © 2015 Wiley Periodicals, Inc.

Despite excellent prognosis, low-grade endometrial stromal sarcoma (ESS) is notorious for late recurrence even in stage I disease. Bone metastases are distinctly rare and only six cases have so far been reported. Two patients presented with back pain due to spinal metastatic low-grade ESS after 15 and 9 years free of disease after resection of the stage 1 primary uterine tumor. Plain radiograph showed an ivory first lumbar vertebra in the first patient and an osteolytic lesion involving the second thoracic vertebra in the second. In both cases, magnetic resonance imaging showed vertebral tumor with intra-spinal extension and spinal cord compression; biopsy confirmed the diagnosis of metastatic low-grade ESS. The first patient received palliative radiotherapy and chemotherapy while the second underwent surgical decompression followed by adjuvant radiotherapy and chemotherapy. The neurologic symptoms in both patients returned 12 months afterwards and progressed relentlessly despite adjuvant chemotherapy and radiotherapy. The first patient developed multiple bone and lung metastasis, culminating in death 44 months after recurrence. While surviving at 24 months from recurrent disease, the second became paraplegic with double incontinence and was wheelchair bound. Delayed osseous metastatic low-grade ESS, although uncommon, deserves recognition given the predilection for spine as the site of involvement. In such a location, where complete surgical removal is notoriously difficult, if not impossible, the prognosis of spinal metastatic low-grade ESS appears grave with considerable morbidity and mortality.

Aim To evaluate the clinical characteristics of primary vaginal sarcoma, which is a rare malignancy Methods We retrospectively reviewed the clinical records of eight patients with primary vaginal sarcoma treated at Sun Yat-Sen University Cancer Centre from 1997 to 2012. Results Eight patients aged ≥17 years were identified (four had leiomyosarcoma, two had endometrial stromal sarcoma, one had undifferentiated sarcoma, and one had adenosarcoma). Four patients had stage I disease, one had stage II, and three had stage IV. Five patients with stage I or II tumor received surgery of mainly local wide excision. One of the five patients received postoperative radiation plus chemotherapy and two had postoperative chemotherapy only. Three of the four stage I patients who had low-grade tumors and received wide local excision were alive without disease at 21, 53, and 81 months, respectively. One stage I patient with a high-grade tumor received simple tumor excision only and died of the disease at 20 months. The patient with stage II disease was lost to follow up. The three stage IV patients received radiotherapy and/or chemotherapy and all died within 2 years. Conclusions Surgery is the main treatment for primary vaginal sarcoma. Prognosis may be associated with tumor grade and stage.

Aims Distinguishing clear cell sarcoma of the kidney (CCSK) from other paediatric malignancies, particularly blastema-rich Wilms tumour (WT) and congenital mesoblastic nephroma (CMN), is challenging. Specific immunohistochemistry for CCSK does not exist, and diagnosis rests upon histopa thology. Recently, the YWHAE–FAM22 rearrange ment, identical to that in endometrial stromal sarcoma (ESS), has been identified in CCSKs. As this fusion results in overexpression of cyclin D1 in ESS, we postulated that overexpression would also occur in CCSK; cyclin D1 immunohistochemistry could then be used to differentiate CCSK from other tumours. The goal of this study was therefore to evaluate the utility of cyclin D1 immunohistochemistry in identifying CCSK and helping to differentiate it from its mimics. Methods and results Cyclin D1 expression was evaluated in 59 renal tumours—CCSK (14), WT (25), rhabdoid tumour (four), Ewing sarcoma (five), and CMN (11)—and four neuroblastomas. All 14 CCSKs showed diffuse and strong reactivity. In contrast, the blastematous component of most WTs showed only rare positive nuclei, that of rhabdoid tumours showed rare to focal immunoreactivity, and that of more than half of CMNs showed weak or focal immunoreactivity. Most Ewing sarcomas and all neuroblastomas showed diffuse moderate to strong staining. Conclusions Cyclin D1 is most helpful in distinguishing CCSK from WT, rhabdoid tumour, and some CMNs, but not from neuroblastoma or Ewing sarcomas.

Background The prognostic significance of oestrogen and progesterone receptors (ER/PR) in endometrial stromal sarcoma (ESS) has conflicting reports in the literature, and the routine use of adjuvant progestogen is of uncertain efficacy. Aims To examine the prognostic significance of ER/PR positivity and of primary adjuvant progestogen use with outcome in ESS. Materials and Methods All women with a diagnosis of ESS in our tertiary institution and associated private practices over the last 23 years were included. Primary variables were ER/PR positivity and adjuvant progestogen use. Other variables included high-grade disease and extrauterine disease. The primary outcome was survival, and the secondary outcome was recurrence-free survival (both overall and at 5 years). Survival was calculated using the Kaplan–Meier method. Univariate analyses were performed with t-test for means and chi-squared test for proportions, and multivariate analysis was used to control for age. Results 35 women were included. ER/PR positivity was associated with a survival benefit (OR death 0.22, P = 0.02), but primary adjuvant progestogen was not. High-grade disease (OR 13, P = 0.02) and extrauterine disease (OR 8.7, P = 0.04) were associated with decreased survival. No variable significantly affected recurrence-free survival. Eight of ten cases of recurrence treated with progestogen have survived more than 3 years. Conclusions ER/PR positivity appears to be useful for prognosis, but routine administration of primary adjuvant progestogen is not supported. There may be a role for progestogen in ER/PR positive tumours with recurrence or incomplete surgical clearance, but further research is required.

Several cases of the uterus being preserved after diagnosis of endometrial stromal sarcoma (ESS) have been reported. Most of these patients were alive and did not experience relapse, but this might have reflected the short follow-up period, given the indolent recurrence of ESS. We report the first fatal case of ESS 10 years after fertility-sparing management. A specimen obtained from the last operation showed loss of estrogen receptor status and expression of c-kit without c-kit or PDGFR-α gene mutations.

Undifferentiated uterine sarcomas (UUS) are rare tumors with a heterologous biology and a poor prognosis. The goal of this study was to examine clinicopathology, biomarkers and YWHAE-FAM22 translocation status, in the prognosis of these tumors. Twenty-six cases of UUS were included. All original slides were rereviewed and age at diagnosis, tumor stage, "Kurihara" diagnosis, mitotic index, presence of necrosis and grade of nuclear atypia were recorded. Additionally, a tissue microarray was constructed from 22 of the cases, and the protein biomarkers P53, P16, Ki-67, Cyclin-D1, ER, PR and ANLN were evaluated by immunohistochemistry. All tumors were evaluated for the presence of a YWHAE-FAM translocation; the translocation was demonstrated in the three Cyclin-D1 positive tumors. Follow-up data in the form of overall survival were available on all patients. These tumors could be divided into two prognostic groups, a high mitotic index group (10 cases, M = 36.8, SD = 5.4) and a low mitotic index group (16 cases, M = 8.7, SD = 5.8). These two groups showed a statistically significant difference in prognosis. The expression of ER, PR or presence of the YWHAE-FAM22 translocation correlated with low mitotic index and an additionally improved prognosis, although the number of cases was small. These results indicate that UUS can be divided into two prognostic groups using mitotic index as a primary criteria, followed by expression of either ER, PR or the presence of a YWHAE-FAM22 translocation as a secondary criteria. This study demonstrates the presence of statistically significant prognostic subgroups within UUS, and provides treatment insights.

Endometrial stromal tumors (ESTs) are composed of cells resembling endometrial stroma, and are divided into benign and malignant types based on morphology. Endometrial stromal nodule (ESN) is a benign localized tumor, and endometrial stromal sarcoma (ESS) is an infiltrative and potentially metastatic neoplasm. A series of genetic aberrations contribute to pathological diagnosis of ESTs. At present, subsets of ESN and ESS-low grade (ESS-LG) are characterized as JAZF1-SUZ12/JJAZ1 gene fusion. The ESTs that show higher grade atypia but lack nuclear pleomorphism include YWHAE-FAM22 ESS. Here we report an unusual case of ESTs. Sudden colonic perforation occurred to the patient, and emergency surgery was performed. Pathological findings suggested metastatic ESS. Thorough medical examination of the genital organs detected a 1 cm-sized well-demarcated uterine tumor. Microscopically, the tumor lacked infiltrative features, conforming to the definition of ESN. Both lesions demonstrated identical cytology and shared JAZF1-SUZ12 gene fusion. Endometriosis was not found in any areas of the resected organs, strongly suggesting that the uterine orthotopic tumor metastasized. The current case uncovered the problems of differential diagnosis between ESN and ESS-LG. We demonstrate detailed pathological features of the two lesions, and discuss the possibility of orthotopic EST with limited infiltration to develop into ESS-LG.

PHF1 gene rearrangements have been recently described in around 50% of ossifying fibromyxoid tumors (OFMT) including benign and malignant cases, with a small subset showing EP400-PHF1 fusions. In the remaining cases no alternative gene fusions have been identified. PHF1-negative OFMT, especially if lacking S100 protein staining or peripheral ossification, are difficult to diagnose and distinguish from other soft tissue mimics. In seeking more comprehensive molecular characterization, we investigated a large cohort of 39 OFMT of various anatomic sites, immunoprofiles and grades of malignancy. Tumors were screened for PHF1 and EP400 rearrangements by FISH. RNA sequencing was performed in two index cases (OFMT1, OFMT3), negative for EP400-PHF1 fusions, followed by FusionSeq data analysis, a modular computational tool developed to discover gene fusions from paired-end RNA-seq data. Two novel fusions were identified ZC3H7B-BCOR in OFMT1 and MEAF6-PHF1 in OFMT3. After being validated by FISH and RT-PCR, these abnormalities were screened on the remaining cases. With these additional gene fusions, 33/39 (85%) of OFMTs demonstrated recurrent gene rearrangements, which can be used as molecular markers in challenging cases. The most common abnormality is PHF1 gene rearrangement (80%), being present in benign, atypical and malignant lesions, with fusion to EP400 in 44% of cases. ZC3H7B-BCOR and MEAF6-PHF1 fusions occurred predominantly in S100 protein-negative and malignant OFMT. As similar gene fusions were reported in endometrial stromal sarcomas, we screened for potential gene abnormalities in JAZF1 and EPC1 by FISH and found two additional cases with EPC1-PHF1 fusions.

Aim Maximum standardized uptake value on 18F-fluorodeoxyglucose positron emission tomography was evaluated as a predictive surrogate marker in developing treatment strategies for recurrent or metastatic endometrial stromal sarcoma. Methods Clinical information was obtained from records of patients with recurrent or metastatic endometrial stromal sarcoma who underwent surgery or biopsy following 18F-fluorodeoxyglucose positron emission tomography. Pathological features – including estrogen receptor, progesterone receptor and Ki-67 expression – were immunohistochemically evaluated. We classified lesions as ‘positron emission tomography positive’ if the maximum standardized uptake value was 3.0 or higher. Clinicopathological features were compared between patients with positive and negative positron emission tomography findings by using the χ2-test. Results Among eight recurrent and one metastatic endometrial stromal sarcoma patients, four (44%) had positron emission tomography-positive findings. Two positron emission tomography-positive patients were estrogen receptor negative and the five positron emission tomography-negative patients were estrogen receptor positive (P = 0.073). The Ki-67 index was 10% or higher in the four positron emission tomography-positive patients, but less than 5% in the five positron emission tomography-negative patients (P = 0.003). Three patients with positron emission tomography-positive tumors received more aggressive treatment (e.g. cytotoxic chemotherapy and additional surgery) than did those with positron emission tomography-negative tumors. One patient who died of disease had positron emission tomography-positive tumors, was negative for estrogen and progesterone receptors, and had a 20% Ki-67 index. Conclusion 18F-Fluorodeoxyglucose uptake was associated with tumor biology of recurrent or metastatic endometrial stromal sarcoma. 18F-fluorodeoxyglucose-positron emission tomography was useful for developing treatment strategies for recurrent or metastatic endometrial stromal sarcoma.

Aims To identify histopathological and immunohistochemical findings that aid diagnosis of metastatic endometrial stromal sarcoma (ESS) in small biopsy specimens of the lung. Methods and results We reviewed the histology of 46 lung nodules from 10 cases of pulmonary metastatic ESS. Biopsy sections were analysed by immunohistochemistry to highlight blood and lymphatic vasculature, and for expression of CD10 and oestrogen receptor (ER). Various histological changes were identified that could mislead in making a diagnosis on small biopsy samples: haemangiopericytomatous blood vessels (39%), absence of characteristic spiral arteriole-like vasculature (26%), intratumoral cysts formed by dilatation of airways (22%) or intratumoral myxoid change (11%), prominent interstitial collagen deposits (48%), foam cell infiltration (4%) and smooth muscle differentiation (2%). Peribronchial/peribronchiolar distribution of tumour cells with juxtaepithelial growth was a frequent feature, observed in 59% of nodules. In two very small nodules the lesion was barely recognizable histologically; tumour cells were detected only by expression of ER and CD10. Conclusions Combined staining for ER and CD10 can be helpful in avoiding an erroneous diagnosis. As lymphatics are not normally present in the juxtaepithelial bronchial/bronchiolar wall, juxtaepithelial tumour growth beneath the bronchial epithelium in early metastatic lesions indicates a haematogenous metastastic route through the bronchial artery.

Sarcomas, including rhabdomyosarcoma (RMS), are rarely encountered in effusion specimens; therefore, difficulties in the accurate diagnosis of metastatic sarcomas in effusions can occasionally arise. Immunohistochemistry for myogenin has emerged as a useful adjunct in the diagnosis of RMS, especially in small biopsy specimens. To date, there are no published series describing the utility of immunocytochemistry for myogenin in the diagnosis of RMS in effusion specimens. A total of 15 patients, for whom metastatic sarcomas were diagnosed in effusion specimens between 1998 and 2012, were identified for analysis: alveolar RMS (n = 5); embryonal RMS (n = 1); pleomorphic RMS (n = 1); angiosarcoma (n = 1); Ewing's sarcoma (n = 2); osteosarcoma (n = 1); endometrial stromal sarcoma (n = 1); unclassified spindle cell sarcoma (n = 1); unclassified/undifferentiated pleomorphic sarcoma (n = 1); and leiomyosarcoma (n = 1). Immunocytochemistry for myogenin was performed for each of these cases as well as for 102 effusions that were positive for metastatic carcinoma. Immunocytochemistry for myogenin diffusely and strongly highlighted the nuclei of the tumor cells in six (86%) of seven cases of metastatic RMS; specifically, the five alveolar RMS and one embryonal RMS cases. The one case of pleomorphic RMS, the eight remaining metastatic sarcoma cases, and all 102 cases of metastatic carcinoma were completely negative for myogenin expression. In conclusion, immunocytochemistry for myogenin is a sensitive and specific ancillary adjunct in the diagnostic evaluation of metastatic RMS in effusion specimens.

A rare case of a mixed endometrial stromal and smooth muscle tumor arising in the uterus of a 74-year-old woman is reported. The patient underwent hysterectomy for an enlarging uterine mass, and a large intramural tumor, showing marked central hyaline necrosis with calcification, was found. The tumor consisted of an admixture of a low-grade endometrial stromal sarcoma (ESS) and a fascicular proliferation of spindle cells suggesting smooth muscle differentiation, and a characteristic 'star-burst' appearance was found. In the ESS region, there were a few small foci of anaplasia where large polygonal cells with atypical nuclei and abundant eosinophilic cytoplasm proliferated, and the proliferative activity was locally increased in these foci. A small metastatic nodule appeared in the lung nine months after the hysterectomy, and the resected metastatic lesion showed features of anaplastic spindle cell sarcoma which was immunoreactive for CD10 but not for smooth muscle markers. Mixed endometrial stromal and smooth muscle tumors should be regarded as malignant neoplasms with the potential for hematogenous metastasis, particularly when they contain foci of cellular anaplasia.

Aims: The aim of this study was to determine the value of morphometric features in distinguishing mild and moderate atypia and predicting the recurrence of World Health Organization 2003-defined endometrial stromal sarcoma and highly malignant undifferentiated endometrial sarcoma. Methods and results: Nuclear and cytological size, shape and arrangement were morphometrically evaluated in 41 cases with consensus no/mild (n = 38) or moderate (n = 3) atypia. None of the cases showed necrosis. The prognostic value of these features in predicting recurrence was also assessed. Seven features differed. The mean and standard deviation of the nuclear volume and the distance between the nuclei were the best discriminators between the no/mild and moderate atypia, with the maximum of the nuclear volume being a practically and rapidly evaluable alternative. With the use of these features, all mild and moderate atypias were correctly classified. Seven cases recurred. The distance between the nuclei and the percentage of nuclei with one neighbour (assessed with morphometric minimum spanning tree analysis) predicted recurrence. Conclusions: In invasive endometrial stromal tumours, morphometric features are useful diagnostic support tools for distinguishing mild from moderate atypia and predicting recurrence.

Aims: Endometrial stromal sarcoma (ESS) has traditionally been divided into low and high grade, but the World Health Organization (WHO, 2003) has changed the definition. Since 2003, many studies have used the old criteria, and few have focused on WHO 2003-defined ESS low grade (ESS-LG). The aim of this study was to investigate prognosticators in ESS-LG. Methods and results: We reviewed the WHO 2003 diagnostic criteria in 91 tumours (previously classified as ESS low and high grade). There were 68 cases of ESS-LG and 23 of undifferentiated endometrial sarcoma (UES). In the ESS-LG cases, the prognostic value of clinicopathological variables was studied. With a median follow-up of 79 months (range: 20–474 months), the recurrence and death rates were 5/68 (7%) and 1/68 (1.5%) in the ESS-LG cases. Ovarian preservation or no ovarian preservation (P 3, P = 0.005, HR 8.6) had independent prognostic value. Other frequently used MAI thresholds – age, tumour diameter, and vessel invasion – were not prognostic. Among patients without ovarian preservation (n = 61), none of 53 with MAI 0–3 suffered recurrence, contrasting with two of eight (25%) of those with MAI >3 (P = 0.003); one of these two recurrence patients died (P = 0.02). Among patients with ovarian preservation (n = 7), three (43%) suffered recurrence but none died, and MAI had no additional prognostic value. Conclusions: In ESS-LG, ovarian preservation and MAI >3 are associated with increased risk of recurrence.

Low-grade endometrial stromal sarcoma (ESS) is a rare neoplasm that is generally estrogen-receptor- and progesterone-receptor-positive and develops in premenopausal women. Although tamoxifen treatment is associated with an increased risk of ESS, the effect of other selective estrogen receptor modulators, including toremifene, on the risk of ESS is not clear. A 61-year-old postmenopausal woman was treated with toremifene as an adjuvant therapy for breast cancer. A cystic mass developed during the treatment, with gradual growth in the uterine myometrium. The patient was treated with hysterectomy and bilateral salpingo-oophorectomy, and the tumor was diagnosed as low-grade ESS (stage IA) with estrogen-receptor and progesterone-receptor. The patient discontinued toremifene and has been progression-free for 21 months. Our data suggest that toremifene might be associated with the development of ESS in certain patients through its estrogen-like effects in the uterus.

Low-grade endometrial stromal sarcoma (LESS) is an uncommon uterine malignancy. Occasionally, it may develop in extrauterine endometriotic lesions and present morphological characteristics mimicking various neoplasms, making its diagnosis very challenging. We report a rare case of a 56-year-old woman presenting with a pelvic mass, initially presumed to be of ovarian origin. After surgical excision the diagnosis of a LESS arising from foci of endometriosis of the terminal ileum was established. Pelvic lymph nodes and omentum were also infiltrated. The patient received adjuvant chemotherapy and medroxyprogesterone; she is alive with no evidence of disease after a follow-up of 38 months. Immunohistochemical characteristics of the tumor are very important for the differential diagnosis of this rare neoplasm and include diffuse strong positivity for CD 10, estrogen receptor expression and CD 34 negativity.

Wong N A C S & Melegh Z (2011) Histopathology59, 781–785 Gastrointestinal stromal tumours can express CD10 and epithelial membrane antigen but not oestrogen receptor or HMB45 Aims: Gastrointestinal stromal tumour (GIST) may share morphological and/or immunohistochemical features with various intra-abdominal neoplasms, including endometrial stromal sarcoma, perivascular epithelioid cell tumour (PEComa), melanoma and synovial sarcoma. Each of these various neoplasms has characteristic immunohistochemical markers, including epithelial membrane antigen (EMA), CD10, oestrogen receptor alpha (ERa) and/or HMB45, and therefore the primary aim of this study was to determine whether these markers are also expressed by GISTs. Methods and results: Standard size sections of 52 GISTs were immunostained for EMA, CD10, ERa and a melanoma marker cocktail (targeting HMB45 and melan-A). Ten GISTs (19%) showed CD10 immunopositivity. This positivity was confined almost completely to small intestinal GISTs, and was seen among spindle cell GISTs but not epithelioid or mixed cell-type GISTs. Five of the 52 GISTs (9.6%) showed EMA immunopositivity. This positivity was always focal and usually seen in a perivascular location. None of the GISTs showed immunopositivity for ERa or the melanoma marker cocktail. Conclusions: GISTs occasionally show CD10 immunopositivity (especially small intestinal spindle cell GISTs), and infrequently show focal EMA positivity. GISTs do not show immunopositivity for ERa or HMB45.

We report a case of high-grade endometrial stromal sarcoma with cytological and immunocytochemical findings. Cytologically, major tumor cells showed round-to-short spindle shapes with round- to oval-shaped nuclei and moderately abundant delicate cytoplasm. Tumor cells with tapered shapes and eccentric nuclei were also observed. A few spindle cells having enlarged cigar-shaped nuclei with conspicuous nucleoli and delicate wispy cytoplasm, which resembled leiomyosarcoma, were intermingled. One rhabdomyoblast cell with both α-sarcomeric muscle actin and myoglobin was also observed. Most of the tumor cells, including the leiomyosarcomatous spindle cells, were positive for CD10, and negative for desmin and h-caldesmon. Accordingly, when relatively monotonous round-to-short spindle tumor cells and taper-shaped tumor cells are observed in the female genital tract, high-grade endometrial stromal sarcoma should be considered in the differential diagnosis. Immunocytochemistry contributed to the correct diagnosis. This case was high-grade endometrial stromal sarcoma with smooth muscle and skeletal muscle differentiation.

Plexiform angiomyxoid myofibroblastic tumor (PAMT) is a relatively recently described gastric tumor with a peculiar plexiform growth pattern. PAMT is typified by a myofibroblastic immunophenotype that distinguishes it from the more common gastrointestinal stromal tumors and the rarely documented fibromyxomas. We report an additional PAMT, the seventh tumor with this label, which was an incidental finding on abdominal computed tomography scan of a 35-year-old Indian female. The tumor measured 4 x 3 x 2 cm and demonstrated plexiform architecture, myxoid stroma, prominent vasculature and spindled cells with myofibroblastic differentiation. The clinicopathological features, progesterone immunopositivity, hitherto undocumented, and mimicry of other primary and secondary gastric mesenchymal tumors, including endometrial stromal sarcoma, are discussed.

A case of endometrial stromal sarcoma associated with the use of an IUCD is to be added to our previous report which included 4 cases of uterine malignancies developing after long-term use of IUCD. In the present case, the IUCD (Lippes loop and nylon ring) had been used for 6 years with interruptions of 1–6 months. When the IUCD is associated with irregular bleeding, it is important to emphasize that besides irregular bleeding as a complication of IUCD, abortion, ectopic pregnancies and uterine malignancies should also be taken into consideration. Endometrial stromal sarcoma is a very rare uterine malignancy, therefore, the association of this tumor with IUCD must count as a great rarity. A case of this kind has never before appeared in the literature.

In our 2 previous papers published in this Journal, we had 5 cases of uterine malignancies developing after long term use of IUCD's. In the present paper 2 cases of such association are to be added. One case ATH with right adnexectomy was performed for persisting vaginal bleeding after 22 years of Lippes Loop application and recurrence 8 years after the first operation. Pathological diagnosis is endometrial stromal sarcoma. The other case is a leiomyosarcoma developing after 25 years of Lippes Loop application. Although no cause and effect relationship between IUCD use and uterine malignancy in human beings has been proved, the increase in such cases suggests to us that long term application should be avoided, particularly in view of the positive animal experiments. The successive detection of such cases in a relatively short period of time prompts us to make further studies to gain a deeper insight into such associations.

Objective To evaluate the clinicopathologic data and prognostic factors for patients with uterine sarcomas treated at a single institution, with special emphasis on malignant mixed mullerian tumors (MMMT). Methods Medical and anatomic pathology records were reviewed. Survival rates were analyzed using the Kaplan-Meier method. Results The study included 89 patients: 48.4% with MMMT; 22.4% with leiomyosarcomas; 20.2% with endometrial stromal sarcomas; and 9% with adenosarcomas. FIGO stages I, II, III, and IV were identified in 57.3%, 9.0%, 22.5%, and 7.8% of patients respectively. Event-free survival rates after 2, 5, and 10 years were 70%, 61%, and 55% respectively, with a median time of 90 months (95% CI, 41–140 months). Overall survival rates after 2, 5, and 10 years were 50%, 45%, and 39% respectively, with a median time of 43 months (95% CI, 3–83 months). Multivariate analysis showed that stage, histology, tumor size, and parity had an independent influence on overall survival. Conclusions MMMT are the most aggressive tumors and their behavior strongly resembles that of high-grade endometrial adenocarcinoma. Prognostic factors affecting survival were stage, histology, tumor size, and parity.

BACKGROUND: The objective of this study was to determine the efficacy of mifepristone (RU-486) in women with advanced or recurrent endometrioid adenocarcinoma or low-grade endometrial stromal sarcoma (LGESS). METHODS: Mifepristone (RU-486; 200 mg orally) was given daily to patients with progesterone receptor-positive advanced or recurrent endometrioid adenocarcinoma or LGESS. Patients were evaluated every 4 weeks for toxicity and response. Quality-of-life data were obtained using the Memorial Symptom Assessment Scale and Functional Assessment for Cancer Therapy. RESULTS: Twelve of 13 enrolled patients were evaluable in the first phase of accrual. Stable disease was noted in 3 of 12 patients (at 8 weeks, 12 weeks, and ≥77 weeks, respectively), and the median time to disease progression was 48 days. Among the patients who had stable disease, 2 women had endometrioid endometrial cancer, and 1 woman had LGESS. No partial or complete responses were observed. The most frequent grade 1 and 2 toxicities were anorexia, fatigue, and mood alterations observed in 50%, 50%, and 58% of patients, respectively. The most common grade 3 toxicities were fatigue and dyspnea observed in 25% and 17% of patients, respectively. One patient experienced grade 4 dyspnea. Thirty-three percent of patients had asymptomatic elevations of corticotropin. No serious treatment-related adverse events occurred. There were no significant changes in quality of life. CONCLUSIONS: Single-agent mifepristone used in the treatment of recurrent endometrioid adenocarcinoma or LGESS resulted in a stable disease rate of 25%. One patient who had a biopsy-positive disease recurrence remained stable at 77 weeks. Although mifepristone was tolerated well, as a single agent, it provided limited response as a single agent in women with progesterone receptor-positive uterine tumors. Recently, was been recognized that biologic agents used as single agents may result only in stable disease unless they are combined with cytotoxic agents. The authors concluded that further research into the best mode of application for mifepristone in the treatment of endometrial cancer is needed. Cancer 2009. © 2009 American Cancer Society.

Endometrial stromal sarcomas are rare and molecular mechanisms involved in their pathogenesis are poorly understood. Covalent modifications of histone proteins, in particular de/acetylation of lysine residues, play an important role in the regulation of gene transcription in normal and neoplastic cells, but there are only limited data about these processes in solid mesenchymal tumours. We treated endometrial stromal sarcoma cells (ESS-1) and non-malignant human endometrial stromal cells (HESCs) with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor. SAHA was able to mediate the cell cycle and expression of genes related to the malignant phenotype of endometrial stromal tumours, eg p21(WAF1) and HDAC7. SAHA led to dose-dependent differentiation and death of ESS-1 cells but not of HESCs. Exposure of HESCs to SAHA resulted only in slightly decreased cell proliferation. SAHA also increased the p21(WAF1) expression and caused significant changes in the cell cycle by inhibiting the G1/S transition in ESS-1 cells. Recovery experiments indicated that these changes became irreversible when the tumour cells were treated with SAHA for longer than 24 h. In our experimental system, not apoptotic but autophagic processes were responsible for the cell death. Monodansyl cadaverine accumulation in treated ESS-1 cells and decreased expression of the mTOR and phospho-S6 ribosomal protein (S6rp) additionally supported this observation. Taken together, our study indicates that HDACs might be considered as potential drug targets in the therapy of stromal sarcomas and that SAHA might be a promising therapeutic agent for endometrial stromal sarcoma.