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High-grade endometrial stromal sarcoma. (A) Gross photo: polypoidal mass. (B) Infiltrative growth with invasion into myometrium (haematoxylin and eosin [H&E], ×100). Inset – non-cohesive uniform round cells (H&E, ×400). (C) CD10 negative (×400). (D) Diffuse cyclin D1 positive (×400). (E) YWHAE-FAM22 breakapart probe detecting t(10;17)(q22; p13) translocation. CD10 indicates cluster differentiation 10.
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Introduction
Endometrial stromal sarcomas (ESSs) are rare and characterized by translocations t(7;17)(p15;q11.2) and t(10;17)(q22;p13), resulting in JAZF1-SUZ12 and YWHAE-FAM22 gene fusions used for defining low-grade (LG-ESS) and high-grade (HG-ESS) tumours.
Aim
The objective of the study was to characterize ESSs using immunohistochemical and mol...
Citations
... Finally, UUS exhibits myometrial invasion, severe nuclear pleomorphism, high mitotic activity and/or necrosis, and loss of differentiation. This tumor, however, does not show a specific immunohistochemical profile, instead showing a diffused and atypical staining for CD10 as well as heterogeneous patterns of ER and PR staining [14,80]. ...
... The latter constitutes a PRC1 variant containing BCOR and KDM2B [154][155][156][157]. Translocations or chromosomal rearrangements, involving fusion proteins have also been implicated in PRCs mechanisms. Fusions such as KDM2B-CREBBP [158], ZC3H7-BCOR [79,155,156,159,160], JAZF1-BCORL1 [79,91,161], EPC1-BCOR [72,95], LPP-BCOR [72] and BCOR internal tandem duplications (BCOR-ITD) are frequently found in ESS, and have recently been also found in LMS samples [80,160,162,163]. Additionally, gene fusion such as MBTD1-CXorf67 [79,91,151,164], MBTD1-EZHIP [90] and MBTD1-PHF1 in ESS are found as products of PRC1-associated protein [152]. ...
There is a consensus that epigenetic alterations play a key role in cancer initiation and its biology. Studies evaluating the modification in the DNA methylation and chromatin remodeling patterns, as well as gene regulation profile by non-coding RNAs (ncRNAs) have led to the development of novel therapeutic approaches to treat several tumor types. Indeed, despite clinical and translational challenges, combinatorial therapies employing agents targeting epigenetic modifications with conventional approaches have shown encouraging results. However, for rare neoplasia such as uterine leiomyosarcomas (LMS) and endometrial stromal sarcomas (ESS), treatment options are still limited. LMS has high chromosomal instability and molecular derangements, while ESS can present a specific gene fusion signature. Although they are the most frequent types of “pure” uterine sarcomas, these tumors are difficult to diagnose, have high rates of recurrence, and frequently develop resistance to current treatment options. The challenges involving the management of these tumors arise from the fact that the molecular mechanisms governing their progression have not been entirely elucidated. Hence, to fill this gap and highlight the importance of ongoing and future studies, we have cross-referenced the literature on uterine LMS and ESS and compiled the most relevant epigenetic studies, published between 2009 and 2022.
... Estos hallazgos son similares a los encontrados por Subbaraya et al. [38], en el que se estudiaron 552 casos de neoplasias endometriales, de los cuales 10 resultaron ser ESS indicando que CD10 tuvo una sensibilidad del 100% y una especificidad del 90% y el receptor de estrógeno (ER) / receptor de progesterona (PR) mostró una sensibilidad y especificidad del 80% y 100% respectivamente en el diagnóstico de LG-ESS, mientras que en el caso de HG-ESS, la inmunohistoquímica fue positiva fuerte para ciclina D1 (mayor al 70% de núcleos) y fueron negativos para CD10, ER y PR. Por lo tanto, las pruebas moleculares fueron útiles en el diagnóstico diferencial de los sarcomas uterinos y es pertinente subclasificarlos en vista de la variedad de pronóstico y manejo [38]. ...
... Estos hallazgos son similares a los encontrados por Subbaraya et al. [38], en el que se estudiaron 552 casos de neoplasias endometriales, de los cuales 10 resultaron ser ESS indicando que CD10 tuvo una sensibilidad del 100% y una especificidad del 90% y el receptor de estrógeno (ER) / receptor de progesterona (PR) mostró una sensibilidad y especificidad del 80% y 100% respectivamente en el diagnóstico de LG-ESS, mientras que en el caso de HG-ESS, la inmunohistoquímica fue positiva fuerte para ciclina D1 (mayor al 70% de núcleos) y fueron negativos para CD10, ER y PR. Por lo tanto, las pruebas moleculares fueron útiles en el diagnóstico diferencial de los sarcomas uterinos y es pertinente subclasificarlos en vista de la variedad de pronóstico y manejo [38]. ...
... Pese a que el estudio del tejido endometrial mediante legrado y biopsia en ocasiones no es concluyente y se requiere de un análisis post quirúrgico tras extracción de la pieza, continúa siendo el pilar fundamental, determinando las características histológicas que definen a la lesión como ESS. Además, el empleo de la inmunohistoquímica es fundamental ya que permite determinar si se trata de una neoplasia de alto o bajo grado, de esta forma, según los estudios se determina que el panel que incluye CD10, Vimentina, ER, PR y ciclina D1, podría determinar el tipo de ESS presente [38]. ...
Introducción: Los sarcomas uterinos representan del 3 al 7% de las neoplasias femeninas y debido a su rareza, etiología desconocida y aberración genética existe falta de consenso sobre los factores de ocurrencia y opciones terapéuticas. Los tumores del estroma endometrial representan menos del 1% y se dividen en cuatro categorías reconocidas por la Organización Mundial de la Salud: nódulo del estroma endometrial, sarcoma del estroma endometrial de bajo grado, sarcoma del estroma endometrial de alto grado y sarcoma uterino indiferenciado. La histerectomía total con salpingooforectomía bilateral es la principal línea de tratamiento. Objetivo: Realizar una revisión bibliográfica actualizada de la fisiopatología, incidencia, cuadro clínico, diagnóstico y tratamiento, del sarcoma uterino endometrial, con el propósito de identificar el estado de conocimiento y resolución de esta patología a nivel mundial. Metodología: Se realizó una búsqueda bibliográfica en las bases de datos: PUBMED, CANCERLIT, EMBASE, BIREME e HINARI, seleccionando artículos publicados en los últimos 10 años, en cualquier idioma, los cuales no fueron limitados por diseño o número de pacientes notificados, que hagan referencia a información precisa sobre el sarcoma endometrial. Resultados: Se identificaron 68 artículos útiles, 47 cumplieron con los criterios de elegibilidad de los cuáles se desprende que la inmunohistoquímica determina el diagnóstico definitivo y que la recurrencia depende del tipo de sarcoma endometrial identificado. Conclusión: El sarcoma endometrial es una neoplasia infrecuente, con manifestaciones clínicas variables e inespecíficas, que afecta a mujeres pre y posmenopáusicas. El diagnóstico precoz y la intervención oportuna son necesarios para la supervivencia de las pacientes.
... CD10 antibody is routinely used for the diagnosis of ESTs, ( Figure 3A) and is the most popular antibody used to differentiate LG-ESS from HG-ESSs [54][55][56][57][58]. However, it is well known that CD10 is not specific for the diagnosis of ESTs [59,60] and some ESTs may show negative immunostaining with CD10 [61,62]. ...
... LG-ESSs demonstrate strong expression with ERα ( Figure 3B) [54,[56][57][58]61,[64][65][66][67][68], while ER-beta (ERβ) expression is mainly negative with occasional reported cases showing weak positivity [64]. PR expression positivity has been reported in the majority of cases (>70%), with strong positivity observed in >50% of cases [58,64,69,70] and its positivity is part of the immunohistochemical confirmation of the diagnosis of LG-ESS [54,56,61,[65][66][67]. ...
... The round cell component is positive for Cyclin D1 ( Figure 7B), BCOR, CD117 (c-kit), CD56, and CD99, whereas DOG1 is negative [7,57,63,77,95,96]. Generally, ER and PR are negative, but positive staining has also been reported; CD10 shows variable expression, either positive or negative [7,56,97]. ...
Endometrial stromal tumours (ESTs) are rare, intriguing uterine mesenchymal neoplasms with variegated histopathological, immunohistochemical and molecular characteristics. Morphologically, ESTs resemble endometrial stromal cells in the proliferative phase of the menstrual cycle. In 1966 Norris and Taylor classified ESTs into benign and malignant categories according to the mitotic count. In the most recent classification by the WHO (2020), ESTs have been divided into four categories: Endometrial Stromal Nodules (ESNs), Low-Grade Endometrial Stromal Sarcomas (LG-ESSs), High-Grade Endometrial Stromal Sarcomas (HG-ESSs) and Undifferentiated Uterine Sarcomas (UUSs). ESNs are clinically benign. LG-ESSs are tumours of low malignant potential, often with indolent clinical behaviour, with some cases presented with a late recurrence after hysterectomy. HG-ESSs are tumours of high malignant potential with more aggressive clinical outcome. UUSs show high-grade morphological features with very aggressive clinical behavior. With the advent of molecular techniques, the morphological classification of ESTs can be integrated with molecular findings in enhanced classification of these tumours. In the future, the morphological and immunohistochemical features correlated with molecular categorisation of ESTs, will become a robust means to plan therapeutic decisions, especially in recurrences and metastatic disease. In this review, we summarise the morphological, immunohistochemical and molecular features of ESTs with particular reference to the most recent molecular findings.
Introdução: Sarcomas do estroma endometrial são raros, originando-se no tecido de sustentação das glândulas endometriais. Classificam-se em baixo grau (SEEBG), alto grau e indiferenciado. Os SEEBGs, agressivos, costumam apresentar sintomas, como sangramento uterino anormal, dor pélvica e dismenorreia. Relato do caso: Mulher de 44 anos, inicialmente diagnosticada com leiomioma epitelioide; dois anos mais tarde, em avaliação histopatológica, o mioma pariu, sugerindo SEEBG. Histerectomia total confirmou o diagnóstico por imuno-histoquímica. Houve metástases para fígado, pulmões, ovários, linfonodos e cavidade peritoneal, levando a paciente a óbito. Conclusão: O diagnóstico é desafiador, frequentemente confundido com outros tumores. Metástases extragenitais podem surgir anos depois do diagnóstico inicial, exigindo acompanhamento contínuo.
Diagnosing low-grade and high-grade endometrial stromal sarcoma (LG-ESS and HG-ESS) is a challenge. This study aimed to identify biomarkers. 22 ESS cases were analyzed using Illumina microarrays. Differentially expressed genes (DEGs) were identified via Limma. DEGs were analyzed with String and Cytoscape. Core genes were enriched with GO and KEGG, their pan-cancer implications and immune aspects were studied. 413 DEGs were found by exome sequencing, 2174 by GSE85383 microarray. 36 common genes were identified by Venn analysis, and 10 core genes including RBFOX1, PCDH7, FAT1 were selected. Core gene GO enrichment included cell adhesion, T cell proliferation, and KEGG focused on related pathways. Expression was evaluated across 34 cancers, identifying immune DEGs IGF1 and AVPR1A. Identifying the DEGs not only helps improve our understanding of LG-ESS, HG-ESS but also promises to be potential biomarkers for differential diagnosis between LG-ESS and HG-ESS and new therapeutic targets.
Background: Immunohistochemistry is an adjunct tool in Surgical Pathology. The fast growing use of immunohistochemistry in gynecologic Pathology has revolutionized the fields of tumor diagnostics & research. Objective: The objective of the study was to share & discuss the experience of utility of immunohistochemistry in Gynecologic Pathology, at a tertiary care hospital in Lahore, Pakistan. Patients & Methods: This was a retrospective, descriptive, cross sectional study, carried out at the Pathology Department of Fatima Jinnah Medical University, Lahore. All cases which were diagnosed after the application of immunohistochemistry during the study period from 1st July 2019 to 31st December 2020 were included in the study. Data included age of the patient, marital status, parity, clinical & radiological presentation, histopathological findings & differentials, list of immunohistochemical markers applied to the case with results & final histopathological diagnosis. Data was analyzed using SPSS version 17. Results: A total of 196 cases were included in the study. The age of the patients ranged from 14 years to 82 years with a mean age of 41 ± 7 years. The commonest use of immunohistochemistry was for histological classification of the tumors of the female genital tract, identifying precancerous lesions, differentiating primary from metastatic CA & predicting response to chemotherapy via proliferative index Ki67. The most commonly used immunohistochemical markers were CK, CK7, CK20, CD 3, CD20, ER, PR, VIMENTIN, WT 1, Ki67, CD 117, SMA, INHIBIN, p53 & p63. Practical implication This study shares the experience of use of common immunohistochemical markers in different cases of gynecologic pathology, highlighting & discussing different panels for use in different scenarios, from which other pathologists may benefit. Conclusion: Immunohistochemistry is an important ancillary tool in the evaluation of gynecologic pathology cases. However, it cannot replace conventional histopathology. It should always be used as an adjunct to histopathology, in the proper clinical & radiological context. Keywords: immunohistochemistry, gynecologic pathology, ovarian carcinoma, leiomyoma, dysgerminoma
Simple Summary
Uterine leiomyosarcoma is an aggressive and rare cancer that is difficult to treat. There are a number of mutations that are common to uterine leiomyosarcoma that are currently not routinely targeted therapeutically in this cancer type. In this review, we summarise the studies being undertaken to investigate the effectiveness of targeting these mutations either pre-clinically in models of uterine leiomyosarcoma or in other cancers in the clinic. We hope this review will encourage the inclusion of uterine leiomyosarcoma in clinical trial design, which in turn will lead to improved survival outcomes for patients.
Abstract
Uterine leiomyosarcoma (uLMS) is a rare and aggressive gynaecological malignancy. Surgical removal and chemotherapy are commonly used to treat uLMS, but recurrence rates are high. Over the last few decades, clarification of the genomic landscape of uLMS has revealed a number of recurring mutations, including TP53, RB1, ATRX, PTEN, and MED12. Such genomic aberrations are difficult to target therapeutically or are actively targeted in other malignancies, and their potential as targets for the treatment of uLMS remains largely unexplored. Recent identification of deficiencies in homologous recombination in a minority of these tumours, however, has provided a rationale for investigation of PARP inhibitors in this sub-set. Here, we review these mutations and the evidence for therapeutic avenues that may be applied in uLMS. We also provide a comprehensive background on diagnosis and current therapeutic strategies as well as reviewing preclinical models of uLMS, which may be employed not only in testing emerging therapies but also in understanding this challenging and deadly disease.
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.
Background
Aromatase inhibitors are standard of care for low-grade endometrial stromal sarcomas (LGESS), based on very high response rates reported in retrospective studies. We evaluated the activity of anastrozole in recurrent/metastatic LGESS patients enrolled in PARAGON, a basket trial of anastrozole in estrogen receptor (ER±)/progesterone receptor (PR+) gynecological cancers.
Method
An investigator-initiated, single-arm, prospective open-label trial of anastrozole 1 mg/day in patients with ER ± PR + ve LGESS with measurable disease, treated until progressive disease or unacceptable toxicity. Primary endpoint was clinical benefit (complete/partial response + stable disease) rate (CBR) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life and toxicity.
Results
15 eligible patients were enrolled. CBR at 3 months was 73% (95% CI: 48–89.1%); unchanged at 6 months. Best response was 26.7%, including complete response in one (6.7%; 95% CI 1.2–29.8%), partial response in three (20%, 95% CI 7.1–45.2%) and stable disease in seven (46.7%). Four patients ceased treatment by 3 months due to progression. Median PFS was not reached (25th percentile: 2.9 months (95% CI: 1.2–NR)). PFS was 73.3%, 73.3% and 66% at 6, 12, and 18 months, respectively. Six patients remained on treatment for an average of 44.2 months (range 34.5–63.6) up until data cut. Toxicity was as expected, with 3 patients stopping due to adverse effects.
Conclusion
The 26.7% objective response rate with anastrozole is lower than reported in retrospective series, but the CBR was high and durable. The results underscore the importance of prospective trials in rare cancers.
