Uterine Mesenchymal Tumors Research Articles

Uterine mesenchymal tumours harboring the KAT6B/A::KANSL1 gene fusion represent a distinct type of uterine sarcoma based on DNA methylation profiles

Uterine mesenchymal tumours harboring KAT6B/A::KANSL1 gene fusions typically exhibit histological and immunophenotypic overlap with endometrial stromal and smooth muscle tumours. To date it remains uncertain whether such neoplasms should be regarded as variants of smooth muscle or endometrial stromal neoplasm, or if they constitute a distinct tumour type. In this study we investigated DNA methylation patterns and copy number variations (CNVs) in a series of uterine tumours harboring KAT6B/A::KANSL1 gene fusions in comparison to other mesenchymal neoplasms of the gynecological tract. Unsupervised hierarchical clustering and t-SNE analysis of DNA methylation data (Illumina EPIC array) identified a distinct cluster for 8/13 KAT6B/A::KANSL1 tumours (herein referred to as core cluster). The other 5 tumours (herein referred to as outliers) did not assign to the core cluster but clustered near various other tumour types. CNV analysis did not identify significant alterations in the core cluster. In contrast, various alterations, including deletions at the CDKN2A/B and NF1 loci were identified in the outlier group. Analysis of the DNA methylation clusters in relation to histological features revealed that while tumours in the core KAT6B/A::KANSL1 cluster were histologically bland, outlier tumours frequently exhibited “high-grade” histologic features in the form of significant nuclear atypia, increased mitotic activity and necrosis. Three of the five patients with outlier tumours died from their disease while clinical follow-up in the remaining two patients was limited (less than 12 months). In comparison, none of the 7 out of 8 patients with tumors in the core KAT6B/A::KANSL1 sarcoma cluster, where follow-up was available, died from disease. Furthermore, only 1 out of 7 patients recurred (mean follow-up of 30 months). In conclusion, KAT6B/A::KANSL1 uterine sarcoma is a molecularly unique type of uterine tumour that should be recognized as a distinct entity. These tumors typically exhibit low-grade histologic features but are occasionally morphologically high-grade; the latter have a DNA methylation profile different from the typical low-grade neoplasms and may be associated with aggressive behaviour.

Uterine Mesenchymal Tumors: Updates on Pathology, Molecular Landscape, and Therapeutics.

Background: Mesenchymal uterine tumors are a diverse group of neoplasms with varying biological potential. Many of these neoplasms can have overlapping morphologic similarities, which, in some instances, render their diagnosis and categorization thorough histomorphologic examination inconclusive. In the last decade, an exponential amount of molecular data aiming to more accurately characterize and, consequently, treat these tumors have accumulated. Objective: The goal of this narrative review is to provide a pathologic review, a genetic update, and to know the new therapeutic avenues of primary uterine mesenchymal neoplasms.

Uterine Tumor Resembling Ovarian Sex-Cord Tumor (UTROSCT): A Rare Polyphenotypic Neoplasm.

Uterine tumor resembling ovarian sex-cord tumor (UTROSCT) is a rare form of uterine mesenchymal neoplasm. Although UTROSCT generally exhibits benign behavior with a favorable prognosis, this neoplasm is nevertheless classified as being of uncertain malignant potential, given its low rate of recurrence and the fact that it rarely produces metastases (e.g., in the lymph nodes, epiploic appendix, omentum, small bowel, subcutaneous tissue, lungs). Its histogenesis is also uncertain. Typically, UTROSCT occurs in peri-menopausal or menopausal women, but it can sometimes be observed in young women. Usually, this neoplasm can be found in the uterine corpus as a nodular intramural lesion, while it is less frequently submucosal, subserosal, or polypoid/intracavitary. UTROSCT can cause abnormal bleeding, pelvic pain, enlarged uterus, and mass sensation, but sometimes it is found purely by chance. This neoplasm can be considered polyphenotypic on morphological, immunohistochemical, and genetic analyses. Generally, upon microscopic examination, UTROSCT shows a predominant pattern of the cords, nests, and trabeculae typical of sex-cord tumors of the ovary, while immunohistochemically it is characterized by a coexpression of epithelial, smooth muscle, and sex-cord markers. The aim of this review is to report clinical and pathological data and genetic alterations to establish their impact on the prognosis and management of patients affected by this rare entity.

The "Other" Uterine Mesenchymal Neoplasms: Recent Developments and Emerging Entities.

Uterine mesenchymal neoplasms are a challenging group of tumors that often show overlapping morphologic features and immunohistochemical profiles. The increasing use of molecular testing in these tumors has enabled a better appreciation of their pathobiology, resulting in a wave of emerging neoplasms and improved characterization of ones previously considered exceptionally rare. Identification of specific molecular alterations has permitted targeted therapy options in tumors that were typically unresponsive to conventional therapies, as well as recognition that a subset can have a hereditary basis. This review will discuss the more "common" of the uncommon uterine mesenchymal neoplasms, including inflammatory myofibroblastic tumor, perivascular epithelioid cell tumor, uterine tumor resembling ovarian sex cord tumor, and embryonal rhabdomyosarcoma. This will be followed by an overview of emerging entities, including NTRK -rearranged uterine sarcoma, SMARCA4 -deficient uterine sarcoma, KAT6B/A::KANSL1 fusion uterine sarcoma, and MEIS1::NCOA2/1 fusion sarcoma.

Ultrasound features using MUSA terms and definitions in uterine sarcoma and leiomyoma: cohort study.

Timely and accurate preoperative diagnosis of uterine sarcoma will increase patient survival. The primary aim of this study was to describe the ultrasound features of uterine sarcoma compared with those of uterine leiomyoma based on the terms and definitions of the Morphological Uterus Sonographic Assessment (MUSA) group. A secondary aim was to assess the interobserver agreement for reporting on ultrasound features according to MUSA terminology. This was a retrospective cohort study of patients with uterine sarcoma or uterine leiomyoma treated in a single tertiary center during the periods 1997-2019 and 2016-2019, respectively. Demographic characteristics, presenting symptoms and surgical outcomes were extracted from patients' files. Ultrasound images were re-evaluated independently by two sonologists using MUSA terms and definitions. Descriptive statistics were calculated and interobserver agreement was assessed using Cohen's κ (with squared weights) or intraclass correlation coefficient, as appropriate. A total of 107 patients were included, of whom 16 had a uterine sarcoma and 91 had a uterine leiomyoma. Abnormal uterine bleeding was the most frequent presenting symptom (69/107 (64%)). Compared with leiomyoma cases, patients with uterine sarcoma were older (median age, 65 (interquartile range (IQR), 60-70) years vs 48 (IQR, 43-52) years) and more likely to be postmenopausal (13/16 (81%) vs 15/91 (16%)). In the uterine sarcoma cohort, leiomyosarcoma was the most frequent histological type (6/16 (38%)), followed by adenosarcoma (4/16 (25%)). On ultrasound evaluation, according to Observers 1 and 2, the tumor border was irregular in most sarcomas (11/16 (69%) and 13/16 (81%) cases, respectively), but regular in most leiomyomas (65/91 (71%) and 82/91 (90%) cases, respectively). Lesion echogenicity was classified as non-uniform in 68/91 (75%) and 51/91 (56%) leiomyomas by Observers 1 and 2, respectively, and 15/16 (94%) uterine sarcomas by both observers. More than 60% of the uterine sarcomas showed acoustic shadows (11/16 (69%) and 10/16 (63%) cases by Observers 1 and 2, respectively), whereas calcifications were reported in a small minority (0/16 (0%) and 2/16 (13%) cases by Observers 1 and 2, respectively). In uterine sarcomas, intralesional vascularity was reported as moderate to abundant in 13/16 (81%) cases by Observer 1 and 15/16 (94%) cases by Observer 2, while circumferential vascularity was scored as moderate to abundant in 6/16 (38%) by both observers. Interobserver agreement for the presence of cystic areas, calcifications, acoustic shadow, central necrosis, color score (overall, intralesional and circumferential) and maximum diameter of the lesion was moderate. The agreement for shape of lesion, tumor border and echogenicity was fair. A postmenopausal patient presenting with abnormal uterine bleeding and a new or growing mesenchymal mass with irregular tumor borders, moderate-to-abundant intralesional vascularity, cystic areas and an absence of calcifications on ultrasonography is at a higher risk of having a uterine sarcoma. Interobserver agreement for most MUSA terms and definitions is moderate. Future studies should validate the abovementioned clinical and ultrasound findings on uterine mesenchymal tumors in a prospective multicenter fashion. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

The Spectrum of Fusions Occurring in Non-Smooth Muscle Mesenchymal Uterine Tumors: A Review of the Current Knowledge.

Non-smooth muscle uterine sarcomas are mostly represented by low-grade endometrial stromal sarcoma. However, several other rare, distinct types of uterine sarcoma are recognized, including high-grade endometrial stromal sarcoma, tumors with kinase fusions, uterine tumors resembling ovarian sex cord tumors, soft tissue-type sarcoma, and emerging entities such as KAT6A/B-rearranged tumors. The landscape of uterine sarcomas has changed, mostly because of the increasing knowledge concerning their molecular aberrations. To offer a comprehensive review of the literature focusing on fusions occurring in other than smooth muscle mesenchymal uterine tumors with respect to their type, frequency, and overlap between diagnostic categories and entities. The data were mined from the PubMed/MEDLINE database covering the time period from January 1988 to June 2023. In total, 156 studies focusing on the problematics of fusions occurring in non-smooth muscle mesenchymal uterine tumors were selected, and thus became the basis for this review. One hundred ten fusions were identified in 703 tumors. The diagnostic significance of the molecular aberrations occurring in these tumors can be unclear in some cases. This can be related to the rare aberrations with a limited number of reported cases. Additionally, even well-known aberrations considered as specific for a certain distinct entity can occur in more lesions, the biological behavior and clinical significance of which can differ substantially.

A Novel EPC1 :: KDM2B Fusion in High-grade Endometrial Stromal Sarcoma.

The spectrum of endometrial stromal sarcoma (ESS) has expanded substantially since the publication of the most recent World Health Organisation (WHO) Classification of Female Genital Tumours and the advent of widely available genomic testing. We describe a uterine mesenchymal tumor harboring a novel EPC1 :: KDM2B fusion, best classified within the umbrella of high-grade endometrial stromal sarcoma (HGESS). This tumor was composed of a uniform population of spindled cells with some myxoid stroma, a mitotic rate of up to 21/10 high-power fields, and a largely pushing margin with focal vascular invasion. Immunohistochemistry showed strong and diffuse cyclin D1 positivity while CD10, WT1, DOG1, CD117, CD34, CD99, S100, MelanA, SMA, desmin, and h-caldesmon were negative. The tumor was confined to the uterus and no recurrence has been detected thus far, albeit with a short follow-up interval of 9mo.

Radiation-Induced Uterine Stromal Sarcoma: A Case Report and Review of the Literature

The radio-induced stromal sarcoma (RISS) is a rare clinical entity, being the second most common type of uterine mesenchymal neoplasm after leiomyosarcoma. Its incidence increases as survival after radiotherapy improves, and it often poses a therapeutic challenge. We report the case of a 58-year-old patient, followed since 2014 for initially classified stage IIb squamous cell carcinoma of the uterine cervix, treated with external pelvic radiotherapy and brachytherapy. After 6 years of surveillance, the patient presented with persistent pelvic pain. Clinical examination and pelvic MRI revealed the presence of a tumoral process in the uterine cervix with suspicious thickening of the endometrium. Morphological and immunohistochemical pathological study of the lesion confirmed its tumoral nature, indicative of a high-grade stromal sarcoma. Radiotherapy can induce malignant tumors after a latent period of several years. Radio-induced gynecological sarcomas are most often associated with a poor prognosis, emphasizing the need for careful and close monitoring after pelvic irradiation.

H3K27me3 deficiency in dedifferentiated carcinoma and carcinosarcoma of the endometrium.

The present study immunohistochemically investigated trimethylation of lysine 27 of histone 3 (H3K27me3) expression in 769 endometrial carcinomas and 196 uterine mesenchymal tumors. One dedifferentiated endometrial carcinoma (DEC) and one carcinosarcoma showed H3K27me3 deficiency that was limited to undifferentiated and sarcomatous components, respectively. Switch/sucrose nonfermenting (SWI/SNF) complex subunits (SMARCA4, SMARCB1, and ARID1A/1B) and mismatch repair proteins were proficient in both tumors. The dimethylation of H3K27 (H3K27me2) was deficient in the undifferentiated component, whereas the sarcomatous component had scattered H3K27me2-positive cells. CXorf67, which inhibits PRC2 function, was diffusely expressed in the sarcomatous component. CXorf67 was negative in the undifferentiated component, which was submitted to a genetic analysis and showed no alterations in PRC2 core subunits or H3K27. The present results suggest H3K27 methylation dysregulation as a cause of SWI/SNF-proficient DEC and carcinosarcoma and imply differences in their level of and the mechanisms underlying H3K27 methylation dysregulation.

Research advances in the different molecular subtypes of uterine mesenchymal tumors

Research advances in the different molecular subtypes of uterine mesenchymal tumors

Uterine mesenchymal tumors: development and preliminary results of a magnetic resonance imaging (MRI) diagnostic algorithm.

The aim of our study is to propose a diagnostic algorithm to guide MRI findings interpretation and malignancy risk stratification of uterine mesenchymal masses with a multiparametric step-by-step approach. A non-interventional retrospective multicenter study was performed: Preoperative MRI of 54 uterine masses was retrospectively evaluated. Firstly, the performance of MRI with monoparametric and multiparametric approach was assessed. Reference standard for final diagnosis was surgical pathologic result (n = 53 patients) or at least 1-year MR imaging follow-up (n = 1 patient). Subsequently, a diagnostic algorithm was developed for MR interpretation, resulting in a Likert score from 1 to 5 predicting risk of malignancy of the uterine lesion. The accuracy and reproducibility of the MRI scoring system were then tested: 26 preoperative pelvic MRI were double-blind evaluated by a senior (SR) and junior radiologist (JR). Diagnostic performances and the agreement between the two readers with and without the application of the proposed algorithm were compared, using histological results as standard reference. Multiparametric approach showed the best diagnostic performance in terms of accuracy (94.44%,) and specificity (97.56%). DWI was confirmed as the most sensible parameter with a relative high specificity: low ADC values (mean 0.66) significantly correlated to uterine sarcomas diagnosis (p < 0.01). Proposed algorithm allowed to improve both JR and SR performance (algorithm-aided accuracy 88.46% and 96%, respectively) and determined a significant increase in inter-observer agreement, helping even the less-experienced radiologist in this difficult differential diagnosis. Uterine leiomyomas and sarcomas often show an overlap of clinical and imaging features. The application of a diagnostic algorithm can help radiologists to standardize their approach to a complex myometrial mass and to easily identify suspicious MRI features favoring malignancy.

Breast metastasis in high-grade endometrial stromal sarcoma (HG-ESS) with BCOR rearrangement: a case report of a novel metastatic site

BackgroundThe ZC3H7B-BCOR fusion gene has recently been described in tumours with kinship to so-called high grade endometrial stromal sarcoma (HG-ESS). This subset of tumour behaves similarly to YWHAE-NUTM2A/B HG-ESS, however, they are both morphologically and immunophenotypically distinct neoplasms. The identified rearrangements in the BCOR gene have been accepted as both the driver and requisite feature in creating a novel sub-entity within the category of HG-ESS.Preliminary investigations into BCOR HG-ESS have shown similar outcomes to YWHAE-NUTM2A/B HG-ESS, with patients typically presenting with high stage disease. Clinical recurrences and metastases to lymph nodes, sacrum/bone, pelvis/peritoneum, lung, bowel and skin have been identified. In this report, we describe a case of BCOR HG-ESS, that is deeply myoinvasive and widely metastatic. Metastatic deposits include a mass in the breast discovered on self-examination; a metastatic site that has yet to be reported in the literature.Case presentationA 59-year-old female underwent biopsy for post-menopausal bleeding, yielding a diagnosis of “low-grade spindle cell neoplasm with myxoid stroma and endometrial glands”, favouring endometrial stromal sarcoma (ESS). She was then referred for total hysterectomy and bilateral salpingo-oophorectomy. The resected uterine neoplasm was both intracavitary and deeply myoinvasive with morphology consistent with that of the biopsy specimen. Characteristic immunohistochemistry (IHC) was noted, and fluorescence in situ hybridization confirmed BCOR rearrangement, supporting a diagnosis of BCOR HG-ESS. A few months postoperatively, the patient underwent needle core biopsy of the breast which revealed metastatic HG-ESS.ConclusionsThis case highlights some of the diagnostic challenges posed by uterine mesenchymal neoplasms, and exemplifies the emerging histomorphologic, immunohistochemical, molecular and clinicopathologic features of the recently described HG-ESS with ZC3H7B-BCOR fusion. It adds to the body of evidence supporting the inclusion of BCOR HG-ESS as a sub-entity of HG-ESS within the endometrial stromal and related tumours subcategory of uterine mesenchymal tumors, as well as the poor prognosis and high metastatic potential of this tumor.

An Unusual Endometrial Stromal Neoplasm With JAZF1-BCORL1 Rearrangement.

Endometrial stromal tumors represent the second most common category of uterine mesenchymal tumors. Several different histologic variants and underlying genetic alterations have been recognized, one such being a group associated with BCORL1 rearrangements. They are usually high-grade endometrial stromal sarcomas, often associated with prominent myxoid background and aggressive behavior. Here, we report an unusual endometrial stromal neoplasm with JAZF1-BCORL1 rearrangement and briefly review the literature. The neoplasm formed a well-circumscribed uterine mass in a 50-yr-old woman and had an unusual morphologic appearance that did not warrant a high-grade categorization. It was characterized by a predominant population of epithelioid cells with clear to focally eosinophilic cytoplasm growing in interanastomosing cords and trabeculae set in a hyalinized stroma as well as nested and fascicular growths imparting focal resemblance to a uterine tumor resembling ovarian sex-cord tumor, PEComa, and a smooth muscle neoplasm. A minor storiform growth of spindle cells reminiscent of the fibroblastic variant of low-grade endometrial stromal sarcoma was also noted but conventional areas of low-grade endometrial stromal neoplasm were not identified. This case expands the spectrum of morphologic features seen in endometrial stromal tumors, especially when associated with a BCORL1 fusion and highlights the utility of immunohistochemical and molecular techniques in the diagnosis of these tumors, not all of which are high grade.

Interceding and Metamorphosed- Endometrial Stromal Sarcoma

Endometrial stromal sarcoma manifests as an infrequently discerned, malignant, high grade uterine mesenchymal neoplasm originating from endometrial stroma and composed of spherical or spindle shaped cells.

Uterine Leiomyosarcoma with a Novel RAB2A-PLAG1 Gene Fusion

Abstract Introduction/Objective Uterine leiomyosarcoma is a malignant neoplasm with three distinct histologic subtypes: spindle, epithelioid, and myxoid. Distinguishing leiomyosarcoma from mesenchymal uterine neoplasms such as endometrial stromal sarcoma can be challenging as they may exhibit a similar histology and immunohistochemical profile. In such cases, molecular studies can help achieve the definitive diagnosis. It has been shown that ~25% of the uterine myxoid leiomyosarcomas harbor TRPS1-PLAG1 and RAD51B-PLAG1 gene fusions. To our knowledge, no uterine leiomyosarcoma with RAB2A-PLAG1 gene fusion has been previously reported in the English literature. Methods/Case Report An 80-year-old woman presented with abnormal uterine bleeding. A large necrotic uterine mass with no evident lymphadenopathy was detected on imaging. Endometrial curettage demonstrated a malignant mesenchymal neoplasm that was positive for CD10, desmin, and vimentin and lacked expression of SMA, SMMH, synaptophysin, and chromogranin. AE1/AE3 highlighted rare foci. The patient underwent total hysterectomy with bilateral salpingo-oophorectomy. The hysterectomy specimen was notable for a 10.8 cm rubbery focally calcified tan- white mass histologically composed of high-grade spindle and epithelioid cells with hypocellular and hyalinized areas. The mitotic activity was &amp;gt;25/10HPF. Immunohistochemically, the neoplastic cells expressed CD10, caldesmon, desmin (patchy), SMA (weak focal), and CAM5.2 (patchy) while they were negative for ER, PR, HMB45, AE1/AE3, WT1, cyclin D1, BCOR, myogenin, pan-NTRK, and ALK. P53 staining showed a wild type expression pattern. Histology and immunohistochemistry could not definitively differentiate between leiomyosarcoma and high grade endometrial stromal sarcoma. RNA sequencing identified a RAB2A-PLAG1 gene fusion. In light of the histology and ancillary studies, a diagnosis of leiomyosarcoma was rendered. Results (if a Case Study enter NA) NA Conclusion This is the first case of a uterine leiomyosarcoma with RAB2A-PLAG1 gene fusion. Pathologists should be cognizant of the extensive morphologic and immunophenotypic overlap between various uterine mesenchymal neoplasms. In challenging cases, molecular analysis is crucial in allowing the pathologist to arrive at the final diagnosis.

Expression of immune checkpoint regulators, programmed death-ligand 1 (PD-L1/PD-1), cytotoxic T lymphocyte antigen 4 (CTLA-4), and indolaimine-2, 3-deoxygenase (IDO) in uterine mesenchymal tumors

BackgroundImmune checkpoints including programmed death-ligand 1/programmed death-1/ (PD-L1/PD-1), cytotoxic T lymphocyte antigen 4 (CTLA-4), and indolaimine-2, 3-deoxygenase (IDO) have recently emerged as effective candidates for treatment against a range of human malignancies. We have investigated their expression in the uterine mesenchymal tumors.MethodsSixty-eight mesenchymal tumors were categorized into 6 diagnostic groups. We assessed PD-L1, PD-1, CTLA-4, and IDO expression on paraffin embedded tissue blocks of the uterine tumors using the respective antibodies. Immunohistochemical (IHC) stains were classified as positive when the reactions were present in at least 1% of the cell membranes for PD-L1/PD-1 or in cytoplasm for CTLA-4 and IDO, regardless of intensity. Student’s t-test and McNemar’s chi-square tests were carried out to analyze the results.ResultsThe mesenchymal neoplasms had expressed the immune checkpoints in the tumor and/or the lymphoid cells at the rate of 49% and 54% respectively. The tumor cells were positive in 10 (18%, PD-L1), 0 (0%, PD-1), 18 (32%, CTLA-4), and 13 (23%, IDO) cases while the infiltrating lymphoid cells were positive in 10 (18%, PD-L1), 23 (40%, PD-1), 18 (32%, CTLA-4), and 13 (23%, IDO) cases. Overall, comparison of paired tumor vs lymphoid cells resulted in p-values of ≤ 0.04.ConclusionsNearly 50% of the uterine tumors express at least one of the immune checkpoints in tumor and/or the infiltrating lymphoid cells. However, expression of the proteins in the two cellular components are mutually exclusive. Namely, when tumor cells express an immune checkpoint, the infiltrating lymphoid cells do not, and vice versa. Since the leiomyosarcomas are reportedly resistant to the immunotherapy when PD-L1 is expressed in the tumor cells, it can be posited that presence of the IHC positive lymphoid cells may be a better indicator of response to the treatment.

Recurrent KAT6B/A::KANSL1 Fusions Characterize a Potentially Aggressive Uterine Sarcoma Morphologically Overlapping With Low-grade Endometrial Stromal Sarcoma.

With the widespread application of next-generation sequencing, the genetic landscape of uterine mesenchymal neoplasms has been evolving rapidly to include several recently identified fusion genes. Although chromosomal rearrangements involving the 10q22 and 17q21.31 loci have been reported in occasional uterine leiomyomas decades ago, the corresponding KAT6B::KANSL1 fusion has been only recently identified in 2 uterine tumors diagnosed as leiomyoma and leiomyosarcoma. We herein describe 13 uterine stromal neoplasms carrying a KAT6B::KANSL1 (n=11) and KAT6A::KANSL1 (n=2) fusion. Patient ages ranged from 33 to 81 years (median, 49 y). Tumor size was 2.6 to 23.5 cm (median, 8.2 cm). Nine tumors were myometrium-centered, and 3 had an intracavitary component. Original diagnoses were mostly low-grade endometrial stromal sarcoma (LG-ESS; 10 cases) with atypical features (limited CD10 expression, sex cord-like features, pericytic vasculature, and frequent myxoid changes). Treatment was hysterectomy±bilateral salpingo-oophorectomy (10), myomectomy (1), and curettage (2). Five patients were disease-free at 6 to 34 months, 3 (27%) died of disease at 2 to 47 months, and 3 were alive with disease at 2, 17, and 17 years. Histologically, most tumors showed variable overlap with LG-ESS, but they were generally well-circumscribed lacking the extensive permeative and angioinvasive growth typical of LG-ESS. They were composed of monotonous medium-sized oval and spindle cells arranged into diffuse sheets with prominent spiral-type arterioles and frequent pericytoma-like vascular pattern. Variable myxoid stromal changes were frequent. Mitotic activity ranged from 1 to >20 in 10 HPFs. Immunohistochemistry showed variable expression of CD10 (12/13), estrogen receptor (8/11), progesterone receptor (8/11), smooth muscle actin (9/11), desmin (4/12), h-caldesmon (2/10), calretinin (3/8), inhibin (1/7), WT1 (4/7), cyclin D1 (5/11; diffuse in only 1 case), and pankeratin (5/10). This series characterizes a KAT6B/A::KANSL1 fusion-positive uterine stromal neoplasm within the morphologic spectrum of LG-ESS but with atypical features. The relationship of these neoplasms to genuine LG-ESS remains unclear. This molecular subtype of uterine endometrial stromal sarcoma has the potential for an unfavorable clinical course despite the absence of widely invasive growth; nevertheless, analysis of more cases is necessary to delineate the phenotypic spectrum and biological potential of this tumor.

Endometrial Stromal Sarcomas With BCOR Internal Tandem Duplication and Variant BCOR/BCORL1 Rearrangements Resemble High-grade Endometrial Stromal Sarcomas With Recurrent CDK4 Pathway Alterations and MDM2 Amplifications.

The distinction between low-grade and high-grade endometrial stromal sarcomas (LGESS, HGESS) is increasingly defined by genetics. Recently, variant genomic alterations involving BCOR or BCORL1 have been reported in endometrial stromal sarcoma (ESS), although it remains unclear whether these justify a diagnosis of LGESS or HGESS. In this study, we describe clinicopathologic and molecular features of ESS with such alterations to help clarify their classification in the spectrum of ESS. We collected a cohort of 13 ESS harboring variant alteration involving BCOR (6 with internal tandem duplication, 1 with EP300::BCOR fusion, 1 with BCOR::LPP fusion) and BCORL1 ( 4 with JAZF1::BCORL1 fusion, 1 with EPC1::BCORL1 fusion). The median patient age at primary diagnosis was 51 years (range: 18 to 70 y). Median tumor size at primary diagnosis was 9.3 cm (range: 4.5 to 21 cm), and extrauterine disease spread (stage IIIB-C) was present in 27%. The tumors were composed of round to spindled cells with cellularity and cytologic atypia ranging from mild to marked and a median mitotic count of 18/10 HPFs (range: 2 to 85/10 HPFs). At least focally myopermeative growth was noted in 8/8 assessable cases. Of 12 patients with follow-up data (median: 25 mo), 4 patients died of disease and 3 were alive with recurrent disease. Unsupervised hierarchical clustering of DNA methylation data together with a large cohort of uterine mesenchymal tumors that included YWHAE::NUTM2 and Z C3H7B::BCOR HGESS and molecularly confirmed LGESS revealed a common methylation signature for all ESS with variant BCOR and BCORL1 alterations and HGESS with YWHAE::NUTM2 and ZC3H7B::BCOR gene fusion. Copy number analysis revealed amplifications of CDK4 and MDM2 , as well as homozygous deletions of CDKN2A/B and NF1 in a subset of tumors. Our results indicate that ESS with BCOR internal tandem duplication and variant BCOR and BCORL1 rearrangements clinically and molecularly resemble conventional HGESS.

Leiomyoma with nuclear atypia: Rare diseases that present a common diagnostic problem.

Leiomyoma with nuclear atypia describes a group of uterine smooth muscle tumors with a wide range of histologic and clinical presentations and remarkable nuclear atypia. These include fumarate hydratase-deficient leiomyoma (FH-LM), intravenous leiomyomatosis (IV-LM), and leiomyoma with bizarre nuclei (LM-BN). Other uterine mesenchymal tumors, such as perivascular epithelioid tumor (PEComa) and inflammatory myofibroblastic tumors (IMFT) are the mimickers of leiomyoma with nuclear atypia. LM-BN is the primary tumor model with a long history in gynecologic pathology, but the histogenesis of LM-BN remains largely unknown. Differentiating LM-BN from other benign variants, tumors with uncertain malignant potential (STUMP), or fully malignant leiomyosarcoma (LMS) can be diagnostically challenging. Recent progress has improved the diagnosis of many types of leiomyoma with nuclear atypia based on their specific histology and molecular alterations. LM-BN is now a diagnosis of exclusion. In this article, I review the history of leiomyoma with nuclear atypia and compare the clinical, histologic, and molecular features of LM-BN with those of its mimics. In particular, I highlight the current progress made in molecular genetics and pitfalls in the diagnosis of different myogenic tumors with nuclear atypia.

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.