Stromal Nodules Research Articles

Immunohistochemical Expression of Lymphoid Enhancer-binding Factor 1 in Low-grade Endometrial Stromal Tumors.

Endometrial stromal tumors (ESTs) are uncommon uterine mesenchymal lesions. Nuclear expression of β-catenin, an indication of activated Wnt/β-catenin signaling pathway, was described in 50% to 92% of low-grade ESTs, including endometrial stromal nodule and low-grade endometrial stromal sarcoma. Activation of the Wnt/β-catenin signaling pathway leads to the translocation of β-catenin into the nucleus and interaction with the T-cell factor/lymphoid enhancer-binding factor-1 (LEF1) family of transcription factors to regulate cell proliferation, differentiation, migration, and survival. Immunohistochemical analysis of β-catenin and LEF1 was performed in 2 endometrial stromal nodules and 20 low-grade endometrial stromal sarcomas and demonstrated 90.9% and 81.8% positive rates for β-catenin and LEF1, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value of β-catenin and LEF1 were 90.9% versus 81.8%, 81.0% versus 85.7%, 83.3% versus 85.7%, 89.5% versus 81.8%, respectively, in the diagnosis of low-grade ESTs. There is no statistical significance of the performance of β-catenin and LEF1 in all ESTs ( P = 0.664) or in primary or metastatic/recurrent settings ( P = 0.515 and 0.999, respectively). Only 3 smooth muscle tumors showed focal and weak positivity for LEF1. Our results indicate LEF1 can be a useful marker in aiding a diagnosis of low-grade EST and differentiating from smooth muscle tumors alone or in combination with β-catenin.

Diagnostic Value of Combined BCOR, Cyclin D1, and CD10 in Differentiating Endometrial Stromal Sarcoma From Other Uterine Spindle Cell Lesions.

Uterine spindle cell lesions share a dilemmatic overlapped features that needed to be addressed by the pathologist to reach a conclusive accurate diagnosis for its prognostic value and different management decisions. Usage of combined IHC panel can be an aiding guiding tool in this context. The aim of this study is to evaluate the diagnostic value of combined BCOR, Cyclin D1, and CD10 IHC panel in differentiating endometrial stromal sarcoma from other uterine spindle cell lesions. This study included 60 cases categorized into endometrial stromal sarcoma group (ESS) (12 cases high-grade endometrial stromal sarcoma [HGESS] and 18 cases low-grade endometrial stromal sarcoma [LGESS]), malignant uterine spindle cell lesions group (5 cases adenosarcoma [AS], 6 cases leiomyosarcoma [LS], 4 cases carcinosarcoma [CS]), and benign uterine lesions group (5 cases endometrial stromal nodule [ESN], 5 cases leiomyoma, and 5 cases adenomyosis). IHC staining procedure and evaluation for BCOR, Cyclin D1, and CD10 was performed on all studied cases. BCOR IHC staining was positive in all HGESS (12/12) of ESS group cases, with diffuse pattern in 75% of cases. BCOR-diffuse staining pattern was not recorded in any of LGESS (0/18), malignant mesenchymal lesions group (0/15), and also benign lesions group (0/15). Cyclin D1 positivity was observed only in HGESS cases, in parallel with positive-BCOR expression. On the contrary, CD10 was negatively expressed in all HGESS and positive in all LGESS, ESN, and adenomyosis cases. A specificity of 100% and sensitivity of 75% were recorded in differentiating HGESS from malignant mesenchymal lesions (including LMS, AS, and CS) and also HGESS from LGESS when using the combined panel BCOR +ve D /Cyclin D1 +ve / CD10 -ve , considering only the BCOR-diffuse staining pattern. In conclusion, BCOR +ve D /Cyclin D1 +ve /CD10 -ve as a combined panel is 100% specific and with lesser sensitivity in diagnosing HGESS as well as differentiating it from LGESS and other malignant uterine spindle cell lesions.

Vaginal Cellular Angiofibroma: Report of a Rare Case with Literature Review

ABSTRACT Cellular angiofibroma (CA) is a relatively recently described, rare, benign soft tissue tumor that predominantly occurs in the vulvoperineal region. It was first described in 1997 as a mesenchymal-origin tumor composed of connective (fibrous) tissue and blood vessels. We report a case of vaginal CA in a 40-year-old woman who presented with pressure symptoms, incidentally diagnosed with a vaginal mass and clinically suspected as vaginal myoma. This case was diagnosed based on histomorphology and immunohistochemistry and underwent surgical treatment. This tumor was a diagnostic dilemma for other benign and aggressive spindle cell tumors in the same area, such as endometrial stromal nodule, spindle cell lipoma, solitary fibrous tumors, and mixed tumors of the vagina.

Inducible CXCL12/CXCR4–dependent extramedullary hematopoietic niches in the adrenal gland

AbstractAdult hematopoietic stem and progenitor cells (HSPCs) reside in the bone marrow (BM) hematopoietic niche, which regulates HSPC quiescence, self-renewal, and commitment in a demand-adapted manner. Although the complex BM niche is responsible for adult hematopoiesis, evidence exists for simpler, albeit functional and more accessible, extramedullary hematopoietic niches. Inspired by the anecdotal description of retroperitoneal hematopoietic masses occurring at higher frequency upon hormonal dysregulation within the adrenal gland, we hypothesized that the adult adrenal gland could be induced into a hematopoietic-supportive environment in a systematic manner, thus revealing mechanisms underlying de novo niche formation in the adult. Here, we show that upon splenectomy and hormonal stimulation, the adult adrenal gland of mice can be induced to recruit and host functional HSPCs, capable of serial transplantation, and that this phenomenon is associated with de novo formation of platelet-derived growth factor receptor α/leptin receptor (PDGFRα+/LEPR+/–)–expressing stromal nodules. We further show in CXCL12–green fluorescent protein reporter mice that adrenal glands contain a stromal population reminiscent of the CXCL12-abundant reticular cells, which compose the BM HSPC niche. Mechanistically, HSPC homing to hormonally induced adrenal glands was found dependent on the CXCR4–CXCL12 axis. Mirroring our findings in mice, we found reticular CXCL12+ cells coexpressing master niche regulator FOXC1 in primary samples from human adrenal myelolipomas, a benign tumor composed of adipose and hematopoietic tissue. Our findings reignite long-standing questions regarding hormonal regulation of hematopoiesis and provide a novel model to facilitate the study of adult-specific inducible hematopoietic niches, which may pave the way to therapeutic applications.

Integrating spatial transcriptomics and single-cell RNA-sequencing reveals the alterations in epithelial cells during nodular formation in benign prostatic hyperplasia

ObjectiveProliferative nodular formation represents a characteristic pathological feature of benign prostatic hyperplasia (BPH) and serves as the primary cause for prostate volume enlargement and consequent lower urinary tract symptoms (LUTS). Its specific mechanism is largely unknown, although several cellular processes have been reported to be involved in BPH initiation and development and highlighted the crucial role of epithelial cells in proliferative nodular formation. However, the technological limitations hinder the in vivo investigation of BPH patients.MethodsThe robust cell type decomposition (RCTD) method was employed to integrate spatial transcriptomics and single cell RNA sequencing profiles, enabling the elucidation of epithelial cell alterations during nodular formation. Immunofluorescent and immunohistochemical staining was performed for verification.ResultsThe alterations of epithelial cells during the formation of nodules in BPH was observed, and a distinct subgroup of basal epithelial (BE) cells, referred to as BE5, was identified to play a crucial role in driving this progression through the hypoxia-induced epithelial-mesenchymal transition (EMT) signaling pathway. BE5 served as both the initiating cell during nodular formation and the transitional cell during the transformation from luminal epithelial (LE) to BE cells. A distinguishing characteristic of the BE5 cell subgroup in patients with BPH was its heightened hypoxia and upregulated expression of FOS. Histological verification results confirmed a significant association between c-Fos expression and key biological processes such as hypoxia and cell proliferation, as well as the close relationship between hypoxia and EMT in BPH tissues. Furthermore, a strong link between c-Fos expression and the progression of BPH was also been validated. Additionally, notable functional differences were observed in glandular and stromal nodules regarding BE5 cells, with BE5 in glandular nodules exhibiting enhanced capacities for EMT and cell proliferation characterized by club-like cell markers.ConclusionsThis study elucidated the comprehensive landscape of epithelial cells during in vivo nodular formation in patients, thereby offering novel insights into the initiation and progression of BPH.

Pearls and Pitfalls in Applying PI-RADS 2.1

AbstractThe use of Prostate Imaging Reporting and Data System (PI-RADS) with multiparametric magnetic resonance imaging (MRI) has significantly improved the detection of clinically significant prostate cancer (csPCa), but there are certain challenges that the reader may face. This review provides an overview of the pitfalls associated with the PI-RADS system for multiparametric prostate MRI (mpMRI), with suggestions/pearls to help overcome these pitfalls.PI-RADS assessment is hindered by several causes of false positives (FPs) and false negatives (FNs). In addition, there is wide variability in the positive predictive value (PPV) of the PI-RADS system across different centers, highlighting the need for improvement. While the negative predictive value (NPV) for csPCa is generally high, variations exist.This review discusses the pitfalls contributing to FNs, including MRI artifacts, such as susceptibility and motion artifacts. Techniques to optimize image acquisition, such as switching the phase encoding direction and reducing bowel peristalsis, are suggested to mitigate these artifacts. Improper b-value selection for diffusion-weighted imaging (DWI) is another pitfall, emphasizing the importance of using high b-values (≥1,400 s/mm2) to optimize neoplasm detection. Similarly, optimizing window settings to visualize csPCa, correctly positioning the endorectal coil, awareness of rare variants like mucinous adenocarcinoma and cribriform adenocarcinoma, and distinguishing central zone tumors from normal central zone are discussed.This article highlights the common pitfalls causing FPs, such as benign pathologies like prostatitis, granulomatous prostatitis, prostatic abscess, stromal BPH nodules, extruded BPH nodules, and prostatic calcifications. It also discusses the pitfalls related to normal anatomical structures, including the central zone, anterior fibromuscular stroma, thickened surgical capsule, neurovascular bundle, and periprostatic venous plexus. Techniques for carefully evaluating these entities' morphology and distribution of signal abnormalities are described to avoid overdiagnosing these as PCa. The article also addresses the pitfalls related to postintervention changes, including postbiopsy hemorrhage and artifacts caused by the UroLift procedure, while providing recommendations for managing these challenges.Finally, the pitfalls that may be encountered during staging, including evaluation for extraprostatic extension, and pelvic nodal and osseous metastases, are highlighted.

Endometrial stromal tumor presenting as multiple endometrial polyps with limited infiltration; a novel presentation

Abstract Introduction/Objective The 2020 WHO classifies endometrial stromal tumors into endometrial stromal nodule (ESN), low-grade endometrial stromal sarcoma (LGESS), high-grade endometrial stromal sarcoma, and undifferentiated sarcoma. Minimal irregularity of the interface is allowed in ESN (up to 3 foci of <3 mm). In a small number of cases, the irregular interface exceeds the acceptable criteria for ESN but relatively limited compared to most LGESS. These cases are classified as endometrial stromal tumor with limited infiltration. These tumors may recur, and it is best managed as LGESS. Methods/Case Report We report a case of endometrial stromal tumor in a 42-year-old female who presented with abnormal vaginal bleeding. Imaging showed multiple fibroids. She underwent total abdominal hysterectomy and bilateral salpingectomy. On gross examination three endometrial polyps with sharp demarcation from the adjacent myometrium were identified (largest 4 cm). Histology revealed proliferation of uniform small cells with scant cytoplasm and round to oval nuclei with rare mitotic figures in a delicate network of arterioles. Immunostains showed positive staining for CD10 and estrogen receptor while negative for Caldesmon. These polyps were mainly confined to the endometrium with only small foci of irregular border with the myometrium. No vascular invasion, high grade cytologic atypia or necrosis were seen. The tumor showed JAZF1-SUZ12 gene fusion. This case was diagnosed as an endometrial stromal tumor with limited infiltration. Results (if a Case Study enter NA) NA Conclusion In conclusion, endometrial stromal tumors are commonly submucosal or intramural, we report a rare case that presented as multiple endometrial polyps, with very limited myometrium infiltration. To our knowledge, no cases have been reported so far. It is essential to be cognizant of this entity when dealing with polypoid lesions of the endometrium, they may recur and should be managed as LGESS.

ASSESSMENT OF PROLIFERATIVE ACTIVITY OF ENDOMETRIAL STROMAL TUMORS USING AgNOR TECHNOLOGY

Endometrial stromal sarcomas (ESS) are rare neoplasms that arise from the endometrial stroma and account for less than 1% of all uterine malignancies. Diagnosis of ESS can be challenging due to its morphological overlap with other endometrial tumors, such as endometrial stromal nodules and stromal endometriosis. AgNOR count is a marker of cell proliferation and has been proposed as a potential tool for differentiating between different types of endometrial tumors.In this study, we analyzed the AgNOR count in 50 cases of endometrial tumors, including endometrial stromal nodules, stromal endometriosis, low-grade ESS, and high-grade ESS. Our results show that there is a significant difference in the AgNOR count across different types of endometrial tumors, with the mean AgNOR count increasing with the severity of the tumor. Endometrial stromal nodules had the lowest mean AgNOR count, while high-grade ESS had the highest.These findings suggest that AgNOR count may be a useful marker for differentiating between different types of endometrial tumors, including ESS. However, further research will be needed to confirm these findings and explore the clinical utility of this marker in the diagnosis and management of these conditions. Overall, our study contributes to our understanding of the biology of endometrial tumors and provides valuable information that may be useful in the development of diagnostic and treatment strategies for these conditions.

Uterine Endometrial Stromal Tumors With Pure Low-Grade Morphology Harboring YWHAE::NUTM2 Fusions: Report of a Case Series Emphasizing Potential for High-Grade Transformation and Aggressive Behavior.

Uterine endometrial stromal sarcomas (ESS) with YWHAE::NUTM2 gene fusions are typically morphologically high-grade tumors composed of atypical round cells, sometimes associated with a low-grade fibromyxoid component; they are currently included in the category of high-grade ESS (HGESS). We report 5 morphologically pure low-grade endometrial stromal tumors harboring YWHAE::NUTM2 fusions, including 1 endometrial stromal nodule (ESN) and 4 low-grade endometrial stromal sarcomas (LGESS), an association only occasionally reported previously. Patients ranged from 30 to 51 (mean=43) years and tumors from 4.5 to 7.5cm (mean=5.7). All were stage I at diagnosis (confined to the uterus). Microscopically, the 4 LGESS showed extensive "tongue-like" invasion of the myometrium, and the ESN was entirely confined to the endometrium with no myometrial invasion. All tumors were composed entirely of morphologically uniform bland ovoid cells resembling proliferative endometrial stroma. A fibromyxoid component was seen in 1 LGESS and the ESN; in the LGESS, this was the sole component. Atypical round cells characteristic of YWHAE::NUTM2 HGESS were not identified. Mitotic count ranged from <1 to 13 per 10 high-power fields (mean: 3). CD10 was positive in 2/4 (focal), estrogen receptor in 5/5 (focal=1; diffuse=4), progesterone receptor in 5/5 (focal=1; diffuse=4) and cyclin D1 was diffusely positive in 3/4. Follow-up was available in all 5 patients and ranged from 6 to 159 months (mean=72). Two patients with LGESS had recurrent disease at 15 and 155 months; 1 showed predominantly LGESS with rare round cells in the initial recurrence and pure HGESS in a subsequent recurrence, while the other patient's recurrent tumor was predominantly HGESS (90%) in a background of focal fibromyxoid LGESS (10%). Both patients rapidly progressed and died of disease within 5 months of high-grade recurrence. We show that rare cases of morphologically pure low-grade endometrial stromal tumors, some but not all with a fibromyxoid component, harbor YWHAE::NUTM2 fusions and may recur rapidly, with transformation to HGESS and aggressive behavior. Our findings suggest that at least a subset of YWHAE::NUTM2 HGESS evolves from LGESS. We suggest that cyclin D1 and CD10 staining should be performed in all LGESS. Diffuse staining for cyclin D1 and/or negative or focal staining for CD10 should suggest the possibility of a YWHAE::NUTM2 fusion, and appropriate molecular testing should be undertaken. Since no single morphological or immunohistochemical parameter is entirely sensitive for fusion status, we also suggest that testing for a YWHAE::NUTM2 gene fusion should be considered in all cases of LGESS and, if a fusion is present, this should raise the possibility of subsequent high-grade transformation and aggressive behavior, even though such cases should still be categorized as LGESS. Although seemingly rare, ESN and LGESS with YWHAE::NUTM2 fusions may be under-recognized due to a lack of routine fusion testing.

Endometrial Stromal Nodule with Intense Decidual Changes. Findings during Delivery of the Placenta

Background: Endometrial stromal nodules involving the placental membranes are exceptionally rare. Only two cases have been described in the literature. We report a new case of endometrial stromal nodule with intense decidual changes as an incidental finding during delivery of the placenta. Case: A 31-years-old female patient with no history of interest presented after a normal term delivery, a 3.5 x 2.6 x 1cm well circumscribed nodule independent of the placenta and not attached to it. The tumor was asymptomatic and was not identificated ultrasonographically. Microscopically, the neoplastic nodule was composed of spindle and epithelioid cells with extensive eosinophilic cytoplasm with a decidualized appearance without associated glands, except for minimal epithelial remnants in the periphery. Characteristic features of endometrial stromal tumor were identified, such as CD10, WT-1, and progesterone receptor positivity, and an expanding noninfiltrating linear pushing rim. There were also pregnancy-related changes, such as decidualization and myxoid change. The lesion was considered a endometrial stromal nodule with an unusual morphology and increased proliferation rate due to the hormonal stimuli of pregnancy. Conclusion: We report a rare case of an incidental endometrial stromal nodule during delivery of the placenta, representing only the third such case reported in the world literature. In all likelihood, this neoplasm originated from the decidua of the free membranes

Endometrial stromal neoplasia: An uncommon tumor at a tertiary health centre in coastal India

Introduction and Aim: Stromal malignancies of uterus are rare and accounts for 1-3% of all female genital tract malignancies. They are known to pose a diagnostic challenge to the clinicians and the pathologists. They show non-specific clinical features, gross appearance, varying histological and immunohistochemical features. This study highlights the important clinical, morphologic and immunohistochemical features of these tumors. Methodology: Histopathologically diagnosed cases of endometrial stromal neoplasia over a period of 5 years from 2013 to 2017 were retrieved. The cases were analysed based on age, tumor size and histological types. Immunohistochemistry (IHC) was done whenever feasible. Results: During the study period, we found 25 cases of endometrial stromal neoplasia. They were composed of four cases of endometrial stromal nodule (ESN), six cases of low grade endometrial stromal sarcoma (ESS) and three cases of ESS with smooth muscle differentiation. Twelve cases of carcinosarcomas and adenosarcomas and a single case of undifferentiated uterine sarcoma were seen. The mean age at presentation of Mixed epithelial stromal sarcoma (Carcinosarcoma) was 61 years while that of ESS and ESN was 46 and 47 years respectively. The mean size of ESN was 3.6cm (1.5-6cm), ESS was 4.5 cm (2-9.9 cm) and carcinosarcomas was 4.9 cm (2.5-16 cm). Conclusion: Endometrial stromal neoplasia should be diagnosed after proper evaluation of gross morphology, histological features and immunohistochemical findings in correlation with the clinical presentation. In addition, genetic profiling is useful as an ancillary test. The spectrum of endometrial stromal neoplasia is a beginner’s ordeal if not aware of.

Endometrial Stromal Sarcoma in a Young, Nulliparous Woman: A Case Report

Endometrial stromal tumours are tumours of endometrial stromal origin and are classified into Endometrial Stromal Nodule (ESN), Low-Grade Endometrial Stromal Sarcoma (LG-ESS), and High-Grade Endometrial Stromal Sarcoma (HG-ESS). LG-ESS and HGESS are rare tumours, accounting for 1% of uterine malignancies and 10% of uterine sarcomas. These tumours commonly occur in perimenopausal women between the ages of 45 and 50 years. Their incidence is rare in younger women. Endometrial stromal tumours are usually confused with leiomyoma, uterine Leiomyosarcoma (LMS), or other sarcomas. The authors here present a case report of a 28-year-old nulligravid patient who presented with a history of heavy menstrual bleeding and dysmenorrhea for a duration of six months. Ultrasonography of the abdomen and pelvis suggested fibroid with degenerative changes, and Magnetic Resonance Imaging (MRI) indicated leiomyoma variants such as: i) Stromal Tumours of Uncertain Malignant Potential (STUMP)/ atypical/cellular leiomyoma; ii) myxoid degeneration of leiomyoma. To arrive at a definitive diagnosis, myomectomy was performed considering the woman’s young age and nulliparity. Histopathology allowed for a differential diagnosis of LG-ESS, LMS, and cellular leiomyoma. Consequently, the patient underwent total abdominal hysterectomy with left salphingo opherectomy, right salpingectomy, and preservation of the right ovary. The definitive diagnosis is made by histopathological examination coupled with immunohistochemistry of the hysterectomy specimen. Hysterectomy is the definitive treatment of LG-ESS considering their ability to infiltrate and become malignant.

Endometrial Stromal Tumour: Clinicopathological Series of Seven Cases

Endometrial Stromal Tumour (EST) mimics other neoplasms and is difficult to diagnose due to its wide range of morphologies. This is a clinicopathological study of seven cases of EST, which includes Endometrial Stromal Nodule (ESN), Low-grade Endometrial Stromal Sarcoma (LGESS), and High-grade Endometrial Stromal Sarcoma (HGESS). The age ranges from 34 to 75 years. Five out of seven cases presented with abnormal uterine bleeding, abdominal pain, and were radiologically suspected to be leiomyomas. After histopathological and Immunohistochemical (IHC) examination, one was diagnosed as ESN, three as LGESS, and the remaining three cases as HGESS. One case was initially diagnosed as a cellular leiomyoma and experienced multiple recurrences, eventually being diagnosed as HGESS with a fatal outcome within 36 months of the onset of the first symptoms. ESN and LGESS should be differentiated from leiomyoma and leiomyosarcoma. IHC plays an important role in distinguishing these tumours from the more common smooth muscle counterparts.

An Unusual Benign Uterine Stromal Spindle Cell Tumor Harboring JAZF1::BCORL1.

Uterine mesenchymal lesions demonstrate various underlying genomic alterations involving MED12 , JAZF1 , YWHAE , BCOR , and ALK genes, among others. Recent publications describe a subset of high-grade endometrial stromal sarcoma lesions harboring BCORL1 gene aberrations including JAZF1::BCORL1 . Herein, we present an unusual benign endomyometrial spindle cell lesion that defies classificatory efforts by demonstrating mixed histomorphologic and immunohistochemical features of endometrial stromal nodule, leiomyoma, and uterine inflammatory myofibroblastic tumor while harboring a JAZF1::BCORL1 . The lesion was found in a 43-yr-old woman with pelvic pain and heavy menses as a 5.5cm well-circumscribed ulcerated mass fungating from the cervical os. Microscopic examination revealed a polypoid, well-circumscribed, moderately cellular endomyometrial tumor composed by bland spindle cells haphazardly disposed within a slightly edematous stroma enriched by a delicate network of thin-walled vessels that were occasionally encircled by the tumor cells. Unequivocal evidence of tongue-like growth pattern into the myometrium, tumor-type necrosis or increased mitotic activity was not identified after sampling the entire lesion. The lesion showed patchy immunoreactivity for both smooth muscle actin-alpha and desmin while negative for CD10, HMB45, ALK (D5F3), and BCOR. An Archer FusionPlex panel assay demonstrated a fusion involving both exons 4 from the JAZF1 and BCORL1 genes. The JAZF1::BCORL1 has not, to the best of our knowledge, been previously reported in a benign/low-grade mesenchymal uterine lesion.

Endometrial stromal tumors: Diagnostic updates and challenges.

Endometrial stromal tumors are rare uterine mesenchymal tumors of endometrial stromal origin. They are classified into endometrial stromal nodule, low-grade endometrial stromal sarcoma, high-grade endometrial stromal sarcoma, and undifferentiated uterine sarcoma by the current (2020) WHO classification. Correct diagnosis of endometrial stromal tumors is critical for proper patient management. However, due to infrequent encounters, overlapping morphological features and immunohistochemical profiles, the differential diagnoses among endometrial stromal lesions and their morphologic mimics are often challenging. Partially with our own experience, here we review and summarize the tumor morphology, immunohistochemical phenotype, as well as molecular feature of endometrial stromal tumors and key differential diagnoses, emphasizing the newest developments and their utilization in daily practice.

Endometrial and other rare uterine sarcomas : Diagnostic aspects in the context of the 2020 WHO classification

Uterine sarcomas are aheterogeneous group of rare malignancies. Mostly (40-50%), they are leiomyosarcomas, followed by endometrial stromal sarcomas (ESS), low-grade (LG) and high-grade (HG), as well as undifferentiated sarcoma of the uterus (UUS) and adenosarcomas (AS). Other, non-organ-specific tumours such as NTRK-rearranged spindle cell neoplasia, perivascular epithelioid cell tumour (PEComa) and inflammatory myofibroblastic tumour (IMT) are extremely difficult to differentiate.In the most recent WHO classification, endometrial stromal tumours are subdivided as follows: benign, expansively growing endometrial stromal nodule (ESN) with sharp demarcation, the histologically similar-looking LG-ESS with infiltrative growth, the highly malignant HG-ESS and, as adiagnosis of exclusion, the highly aggressive UUS lacking specific lines of differentiation. LG-ESS can be differentiated from HG-ESS in most cases histomorphologically and immunohistochemically, but molecular investigations are necessary in individual cases. HG-ESS can be divided into 4subtypes (YWHAE/NUTM2 fusion low-grade component, YWHAE/NUTM2 fusion high-grade component, ZC3H7B-BCOR fusion or BCOR-ITD) on the basis of molecular findings. Prognostically unfavourable factors in AS are severe sarcomatous overgrowth, deep myometrial invasion, high-grade histology and lymphatic vessel invasion. Tumours with NTRK fusion are immunohistochemically positive for S100 and TRK. PEComas express cathepsin K and HMB45, as well as TFE3 when translocation is present. Almost every IMT shows an alteration in the ALK gene In the case of overlapping morphology and simultaneous therapeutic and prognostic relevance, it is becoming increasingly important to verify or confirm the suspected histomorphological diagnosis by immunohistochemical and possibly molecular investigations.

High-Grade Endometrial Stromal Sarcoma: Molecular Alterations and Potential Immunotherapeutic Strategies.

Endometrial stromal tumor (EST) is an uncommon and unusual mesenchymal tumor of the uterus characterized by multicolored histopathological, immunohistochemical, and molecular features. The morphology of ESTs is similar to normal endometrial stromal cells during the proliferative phase of the menstrual cycle. ESTs were first classified into benign and malignant based on the number of mitotic cells. However, recently WHO has divided ESTs into four categories: endometrial stromal nodules (ESN), undifferentiated uterine sarcoma (UUS), low-grade endometrial stromal sarcoma (LG-ESS), and high-grade endometrial stromal sarcoma (HG-ESS). HG-ESS is the most malignant of these categories, with poor clinical outcomes compared to other types. With advances in molecular biology, ESTs have been further classified with morphological identification. ESTs, including HG-ESS, is a relatively rare type of cancer, and the therapeutics are not being developed compared to other cancers. However, considering the tumor microenvironment of usual stromal cancers, the advance of immunotherapy shows auspicious outcomes reported in many different stromal tumors and non-identified uterine cancers. These studies show the high possibility of successful immunotherapy in HG-ESS patients in the future. In this review, we are discussing the background of ESTs and the BCOR and the development of HG-ESS by mutations of BCOR or other related genes. Among the gene mutations of HG-ESSs, BCOR shows the most common mutations in different ways. In current tumor therapies, immunotherapy is one of the most effective therapeutic approaches. In order to connect immunotherapy with HG-ESS, the understanding of tumor microenvironment (TME) is required. The TME of HG-ESS shows the mixture of tumor cells, vessels, immune cells and non-malignant stromal cells. Macrophages, neutrophils, dendritic cells and natural killer cells lose their expected functions, but rather show pro-tumoral functions by the matricellular proteins, extracellular matrix and other complicated environment in TME. In order to overcome the current therapeutic limitations of HG-ESS, immunotherapies should be considered in addition to the current surgical strategies. Checkpoint inhibitors, cytokine-based immunotherapies, immune cell therapies are good candidates to be considered as they show promising results in other stromal cancers and uterine cancers, while less studied because of the rarity of ESTs. Based on the advance of knowledge of immune therapies in HG-ESS, the new strategies can also be applied to the current therapies and also in other ESTs.

Fibroblastic variant of low grade endometrial stromal sarcoma mimicking an inflammatory pseudotumor: a case report

The World Health Organization currently divides endometrial stromal sarcomas into 4 different entities, based on their clinical and pathological features: endometrial stromal nodule, low-grade endometrial stromal sarcomas (LG-ESS), High-grade endometrial stromal sarcomas, and undifferentiated uterine sarcoma. The fibroblastic variant of LG-ESS is rare and is usually made of small tumoral cells of oval to fusiform shape, demonstrating low cytologic atypia and low mitotic activity, which can lead to confusion with a benign myofibroblastic proliferation. We hereby report a rare case of a fibroblastic variant of LG-ESS in a 37-year-old woman presenting abundant metrorrhagia, which was initially misdiagnosed as an inflammatory pseudotumor before proofreading in our laboratory, along with a review of a histological and immunohistochemical findings, aiming to help pathologists avoid this diagnosis pitfall.

Pleural Metastasis of High-Grade Endometrial Stromal Sarcoma With YWHAE Gene (17p13.3) Rearrangement, A Rare Case Report

Abstract Introduction/Objective Endometrial stromal sarcoma (ESS), a rare malignant neoplasm of endometrial stroma, accounts for less than 1% of all uterine tumors. High grade ESS (HGESS) is aggressive and commonly relapses even after surgical and neoadjuvant therapy. Abdominal and pelvic regions are common sites of metastasis, however, distant metastases to the liver, lung, vertebrae, and brain have been reported. Methods/Case Report We encountered a 49-year-old female who presented with shortness of breath, found to have a left pleural effusion and multiple pleural masses. She initially presented three years ago with heavy irregular menses and left pelvic pain for one year. D&amp;C revealed prominent small spindle cells for which a stromal nodule and low-grade or malignant process was probable. CT scan showed an enlarged uterus. Hysterectomy with bilateral salpingo- oophorectomy, bilateral pelvic and para-aortic lymph node dissection, and partial omentectomy were performed. The uterus revealed an intramural 7 cm mass with a serpiginous growth pattern and lymphovascular invasion. Tumor cells were plump to spindled with areas of high cellularity, rounded nuclei, increased atypia and mitosis. Atypical areas were positive for cyclin D1, focally positive for CD10, and negative for ER, PR, SMA, desmin, AE1/3 and CAM5.2. FISH studies showed rearrangement of YWHAE gene (17p13.3) and no rearrangement of JAZF1 or PHF1 gene regions. Findings supported the diagnosis of HGESS. The patient received post-operative chemotherapy. Biopsy of the current pleural lesion revealed a nonspecific malignant spindle cell neoplasm positive for BCL1, CD56, CD117, CD99, TLE1 and INI1, while negative for AE1/3, CAM5.2, EMA, ER, PR, CK5/6, calretinin, SMA, desmin and S100. The CD10 stain was inconclusive. FISH studies showed rearrangement of YWHAE gene (17p13.3) and no rearrangement involving JAZF1 or PHF1 gene regions. No rearrangement of the SS18 gene region was observed and synovial sarcoma was excluded. Overall findings support the diagnosis of metastatic HGESS. Results (if a Case Study enter NA) NA Conclusion HGESS, a rare tumor with a nonspecific immunostain profile, has the ability to metastasize to rare body sites, such as the pleura in our case. Display of spindle cell morphology is a nonspecific finding that raises broad differential diagnoses. In women, with or without a history of uterine neoplasm, HGESS is a clinically worthwhile diagnosis to be mindful of.

LG-ESSs and HG-ESSs: underlying molecular alterations and potential therapeutic strategies.

Endometrial stromal tumors (ESTs) include endometrial stromal nodule (ESN), low-grade endometrial stromal sarcoma (LG-ESS), high-grade endometrial stromal sarcoma (HG-ESS), and undifferentiated uterine sarcoma (UUS). Since these are rare tumor types, there is an unmet clinical need for the systematic therapy of advanced LG-ESS or HG-ESS. Cytogenetic and molecular advances in ESTs have shown that multiple recurrent gene fusions are present in a large proportion of LG-ESSs, and HG-ESSs are identified by the tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon (YWHAE)-family with sequence similarity 22 (FAM22) fusion. Recently, a group of ESSs harboring both zinc finger CCCH domain-containing protein 7B (ZC3H7B)-B-cell lymphoma 6 corepressor(BCOR) fusion and internal tandem duplication (ITD) of the BCOR gene have been provisionally classified as HG-ESSs. In this review, we firstly describe current knowledge about the molecular characteristics of recurrent aberrant proteins and their roles in the tumorigenesis of LG-ESSs and HG-ESSs. Next, we summarize the possibly shared signal pathways in the tumorigenesis of LG-ESSs and HG-ESSs, and list potentially actionable targets. Finally, based on the above discussion, we propose a few promising therapeutic strategies for LG-ESSs and HG-ESSs with recurrent gene alterations.