RESUMO
BACKGROUND: High-grade endometrial stromal sarcoma (HG-ESS) is a rare malignant tumor with poor prognosis. To overcome the limitations of current treatment for advanced patients, the intervention of targeted drug therapy is urgently needed. CASE PRESENTATION: A 74-year-old married woman who presented with abdominal distension and lower abdominal pain was admitted to Hebei General Hospital. After surgery, immunohistochemical staining revealed a malignant tumor which was consistent with HG-ESS. Tumor recurrence occurred 2 months after surgery. Then the patient underwent chemotherapy with two courses but responded poorly. Subsequently we observed ATM, BLM, and CDH1 co-mutations by Next Generation Sequencing (NGS). Then the patient received pamiparib, which resulted in a 10-month progression-free survival (PFS) and is now stable with the administration of sintilimab in combination with pamiparib and anlotinib. CONCLUSIONS: Due to the successful use of poly ADP-ribose polymerase inhibitor (PARPi) on HG-ESS, we suggest that the selection of effective targeted drugs combined with anti- programmed death-1 (PD-1) drug therapy based on genetic testing may become a new option for the treatment of homologous repair deficient (HR-deficient) HG-ESS.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia , Caderinas , Neoplasias do Endométrio , RecQ Helicases , Sarcoma do Estroma Endometrial , Humanos , Feminino , Idoso , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/patologia , Sarcoma do Estroma Endometrial/genética , Sarcoma do Estroma Endometrial/tratamento farmacológico , Sarcoma do Estroma Endometrial/diagnóstico , Proteínas Mutadas de Ataxia Telangiectasia/genética , RecQ Helicases/genética , Caderinas/genética , Antígenos CD/genética , MutaçãoRESUMO
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.
Assuntos
Neoplasias do Endométrio , Sarcoma do Estroma Endometrial , Feminino , Humanos , Sarcoma do Estroma Endometrial/diagnóstico , Sarcoma do Estroma Endometrial/genética , Biomarcadores Tumorais/metabolismo , Perfilação da Expressão Gênica , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Biologia ComputacionalRESUMO
The landscape of uterine sarcomas is becoming more complex with the description of new entities associated with recurrent driver molecular alterations. Uterine sarcomas, in analogy with soft tissue sarcomas, are distinguished into complex genomic and simple genomic sarcomas. Leiomyosarcomas and undifferentiated uterine sarcomas belong to complex genomic sarcomas group. Low-grade and high-grade endometrial stromal sarcomas, other rare tumors associated with fusion transcripts (such as NTRK, PDGFB, ALK, RET ROS1) and SMARCA4-deficient uterine sarcoma are considered simple genomic sarcomas. The most common uterine sarcoma are first leiomyosarcoma and secondly endometrial stromal sarcomas. Three different histological subtypes of leiomyosarcoma (fusiform, myxoid, epithelioid) are identified, myxoid and epithelioid leiomyosarcoma being more aggressive than fusiform leiomyosarcoma. The distinction between low-grade and high-grade endometrial stromal sarcoma is primarily morphological and immunohistochemical and the detection of fusion transcripts can help the diagnosis. Uterine PEComa is a rare tumor, which is distinguished into borderline and malignant, according to a risk assessment algorithm. Embryonal rhabdomyosarcoma of the uterine cervix is more common in children but can also occur in adult women. Embryonal rhabdomyosarcoma of the uterine cervix is almost always DICER1 mutated, unlike that of the vagina which is wild-type DICER1, and adenosarcoma which can be DICER1 mutated but with less frequency. Among the emerging entities, sarcomas associated with fusion transcripts involving the NTRK, ALK, PDGFB genes benefit from targeted therapy. The integration of molecular data with histology and clinical data allows better identification of uterine sarcomas in order to better treat them.
Assuntos
RNA Helicases DEAD-box , Neoplasias do Endométrio , Neoplasias dos Genitais Femininos , Leiomiossarcoma , Rabdomiossarcoma Embrionário , Ribonuclease III , Sarcoma do Estroma Endometrial , Neoplasias de Tecidos Moles , Neoplasias do Colo do Útero , Neoplasias Uterinas , Adulto , Criança , Feminino , Humanos , Leiomiossarcoma/diagnóstico , Leiomiossarcoma/genética , Leiomiossarcoma/terapia , Rabdomiossarcoma Embrionário/diagnóstico , Rabdomiossarcoma Embrionário/genética , Rabdomiossarcoma Embrionário/terapia , Sarcoma do Estroma Endometrial/diagnóstico , Sarcoma do Estroma Endometrial/genética , Sarcoma do Estroma Endometrial/terapia , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética , Neoplasias Uterinas/terapia , Receptores Proteína Tirosina Quinases , DNA Helicases , Proteínas Nucleares , Fatores de TranscriçãoRESUMO
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.
Assuntos
Neoplasias do Endométrio , Tumores do Estroma Endometrial , Sarcoma do Estroma Endometrial , Neoplasias Uterinas , Feminino , Humanos , Tumores do Estroma Endometrial/diagnóstico , Tumores do Estroma Endometrial/genética , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/química , Sarcoma do Estroma Endometrial/diagnóstico , Sarcoma do Estroma Endometrial/genética , Neoplasias Uterinas/patologia , Útero/patologia , Proteínas de Ligação a DNA/genética , Proteínas Correpressoras/genética , Proteínas Repressoras/genéticaRESUMO
Several defining molecular alterations have recently been identified underlying high-grade endometrial stromal sarcomas, such as YWHAE: NUTM2A/B fusions, ZC3H7B: BCOR fusions, and BCOR internal tandem duplication (ITD). BCOR is a useful immunohistochemical marker for identifying these tumors. A 37-year-old lady was presented with a 10-cm-sized tumor in the pouch of Douglas, involving the vaginal vault, bilateral adnexa, and peritoneum. A 53-year-old lady with a prior hysterectomy was presented with a 12-cm-sized tumor in the vault with abdominal deposits. Histopathological examination of both tumors revealed atypical cells comprising oval to spindle-shaped nuclei, a variable amount of myxoid stroma, and mitotic figures exceeding 10/10 high power fields. Immunohistochemically, the former tumor was diffusely positive for CD10, and the second tumor displayed patchy staining. Both tumors were positive for BCOR. Estrogen receptor (ER) showed variable staining in both tumors. By fluorescence in-situ hybridization (FISH), both tumors lacked YWHAE gene rearrangement. Both tumors had an aggressive clinical course, including extensive involvement This constitutes the first report of BCOR-positive high-grade sarcomas involving the female genital tract from our subcontinent. BCOR is a useful immunostain for identifying these relatively aggressive tumors. The differential diagnoses and the prognosis of these ultra-rare tumors are discussed herewith.
Assuntos
Neoplasias do Endométrio , Sarcoma do Estroma Endometrial , Sarcoma , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Sarcoma do Estroma Endometrial/diagnóstico , Sarcoma do Estroma Endometrial/genética , Proteínas Repressoras/genética , Proteínas Proto-Oncogênicas/genética , Sarcoma/patologia , Biomarcadores Tumorais/genética , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/químicaRESUMO
Endometrial/endometrioid stromal tumors are rare and morphologically heterogenous, and their diagnosis may be challenging. We identified 3 endometrial/endometrioid stromal tumors with identical and previously undescribed histologic features and herein report their morphologic, immunohistochemical, and molecular profiles. Patients were 53, 62, and 79 years. Tumors were well-circumscribed, tan-yellow solid masses measuring 10.0, 11.0, and 18.7 cm, and were intramyometrial (n=2) or in the broad ligament (n=1). All showed small, tight whorls of epithelioid to slightly spindled tumor cells with minimal cytoplasm and negligible mitoses, multifocally associated with hyalinization and myxoid change set in a loose fibroblastic background with small, delicate vessels. This morphology was seen throughout in 1 tumor and in â¼20% and 70% of the 2 others with the remaining areas showing sex cord-like differentiation. Tumor cells expressed CD10 (3/3, 1 focal), calretinin (3/3 diffuse), WT1 (3/3 diffuse), estrogen receptor (1/1, diffuse). RNA-sequencing was successful in 1 tumor and revealed a GREB1-CTNNB1 in-frame fusion. All 3 tumors harbored a CTNNB1 translocation by fluorescence in situ hybridization correlating with nuclear ß-catenin expression. Whole-genome DNA methylation analysis classified all 3 tumors within the low-grade endometrial stromal sarcoma reference class with flat copy number profiles. One patient (79-y-old) died of unrelated causes 2 months after surgery and the other 2 were alive without disease after 13 and 75 months. We have described a rare subset of endometrial/endometrioid stromal tumors with extensive whorling and a CTNNB1 translocation, expanding the morphologic and molecular spectrum of these neoplasms.
Assuntos
Neoplasias do Endométrio , Tumores do Estroma Endometrial , Sarcoma do Estroma Endometrial , Feminino , Humanos , beta Catenina/genética , Hibridização in Situ Fluorescente , Tumores do Estroma Endometrial/patologia , Mitose , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/cirurgia , Neoplasias do Endométrio/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Sarcoma do Estroma Endometrial/genética , Sarcoma do Estroma Endometrial/cirurgia , Sarcoma do Estroma Endometrial/patologiaRESUMO
High-grade endometrial stromal sarcomas with ZC3H7B-BCOR fusion are rare. They are predominantly located in the endomyometrium, with morphologic features characterized as haphazardly arranged fascicles of spindle cells with mild to moderate atypia, abundant myxoid matrix, high mitotic index, and tongue-like/pushing patterns of myometrial invasion. Furthermore, conventional or variant low-grade endometrial stromal sarcomas are often not present. Clinically, they present at a higher stage and are associated with worse prognosis compared with low-grade endometrial stromal sarcoma. Given the limited number of reported cases, we describe the case of a ZC3H7B-BCOR fusion high-grade endometrial stromal sarcoma initially diagnosed on the hysterectomy specimen as low-grade endometrial stromal sarcoma based on an endometrial stromal tumor showing tongue-like myometrial and lymphovascular invasion, minimal cytologic atypia, low-mitotic activity (0-1/10 high-power field), round/spindle cell component and immunohistochemical stain results (positive for CD10, estrogen receptor, progesterone receptor, and focally positive for cyclin D1). At the time of pathologic diagnosis, she was Stage Ia and managed conservatively. Subsequent molecular analysis revealed a ZC3H7B (exon 10)- BCOR (BCL-6 corepressor) (exon 7) gene fusion. On follow-up, she showed no evidence of disease at 37 months from the time of diagnosis. This case report expands the morphologic spectrum of ZC3H7B-BCOR fusion high-grade ESS, which includes an intramural location, morphologic and immunophenotypic features similar to LG-ESS, as well as the presence of round and spindle cell components. This case also underscores the value of molecular analysis in the proper classification of ESS.
Assuntos
Neoplasias do Endométrio , Tumores do Estroma Endometrial , Sarcoma do Estroma Endometrial , Feminino , Humanos , Sarcoma do Estroma Endometrial/diagnóstico , Sarcoma do Estroma Endometrial/genética , Sarcoma do Estroma Endometrial/cirurgia , Tumores do Estroma Endometrial/diagnóstico , Proteínas Repressoras/metabolismo , Neoplasias do Endométrio/genética , Proteínas Proto-Oncogênicas/genética , Fatores de Transcrição , Proteínas de Ligação a RNARESUMO
OBJECTIVES: Low-grade and high-grade endometrial stromal sarcomas (LGESS and HGESS) and undifferentiated uterine sarcomas (UUS) are rare tumors whose pathological classification and staging system have changed recently. These tumors are reported to contain fusion genes. We aimed to clarify the genetic background, clinical features, prognostic factors, and optimal therapy of these tumors using a new classification and staging system. METHODS: We analyzed the clinical features and prognostic information of 72 patients with LGESS, 25 with HGESS, and 16 with UUS using central pathological review. Estrogen and progesterone receptors (PgRs) were examined by immunohistochemistry. JAZF1-SUZ12 and YWHAE-NUTM2A/B gene fusions were tested using real-time polymerase chain reaction. RESULTS: The 5-year overall survival (OS) rates of LGESS, HGESS, and UUS were 94%, 53%, and 25%, respectively. In LGESS, stage IV, incomplete surgery, and absence of PgR were associated with poor OS. The presence of JAZF1-SUZ12 fusion gene was not associated with OS. In HGESS, the relationship between stage and prognosis was unclear. None of the 3 patients with YWHAE-NUTM2A/B fusion gene died during follow-up. Adjuvant chemotherapy was associated with a favorable OS. Incomplete resection of UUS was associated with poor OS; however, residual tumors frequently occurred. Although most patients underwent adjuvant chemotherapy, their prognosis was extremely poor even in stage I disease. CONCLUSIONS: Prognosis of LGESS is generally good; however, stage IV, incomplete surgery, and PgR-negative tumors are associated with poor prognosis. Adjuvant chemotherapy may be useful for HGESS. Prognosis of UUS is extremely poor, even with adjuvant chemotherapy.
Assuntos
Neoplasias do Endométrio , Sarcoma do Estroma Endometrial , Feminino , Humanos , Prognóstico , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/terapia , Neoplasias do Endométrio/patologia , Estudos Retrospectivos , Sarcoma do Estroma Endometrial/genética , Sarcoma do Estroma Endometrial/terapia , Sarcoma do Estroma Endometrial/patologia , População do Leste Asiático , Fatores de Transcrição , OncologiaAssuntos
Neoplasias do Endométrio , Tumores do Estroma Endometrial , Sarcoma do Estroma Endometrial , Feminino , Humanos , Sarcoma do Estroma Endometrial/genética , Fatores de Transcrição/genética , Neoplasias do Endométrio/genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Ligação a DNA , Proteínas do Grupo PolycombAssuntos
Neoplasias do Endométrio , Sarcoma do Estroma Endometrial , Feminino , Humanos , Sarcoma do Estroma Endometrial/genética , Sarcoma do Estroma Endometrial/cirurgia , Fatores de Transcrição/genética , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/cirurgia , Proteínas de Ligação a DNA , Proteínas Correpressoras , Proteínas Repressoras/genéticaRESUMO
BACKGROUND: The 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 PRESENTATION: A 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. CONCLUSIONS: This 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.
Assuntos
Neoplasias da Mama , Neoplasias do Endométrio , Segunda Neoplasia Primária , Sarcoma do Estroma Endometrial , Neoplasias Cutâneas , Feminino , Humanos , Pessoa de Meia-Idade , Sarcoma do Estroma Endometrial/genética , Hibridização in Situ Fluorescente , Fatores de Transcrição , Neoplasias do Endométrio/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Melanoma Maligno CutâneoRESUMO
High-grade endometrial stromal sarcomas (HGESSs) are aggressive uterine tumors harboring oncogenic fusion proteins. We performed a molecular study of 36 HGESSs with YWHAE::NUTM2 gene fusion, assessing co-occurring genetic events, and showed that these tumors frequently harbor recurrent events involving the CDKN2A locus on chromosome 9p. Using array-based copy number profiling and CDKN2A fluorescence in situ hybridization, we identified homozygous and hemizygous deletions of CDKN2A in 18% and 14% of tumors (n = 22 analyzed), respectively. While all YWHAE-rearranged HGESSs with retained disomy for CDKN2A were immunohistochemically positive for p16INK4 (p16), all tumors with homozygous deletion of CDKN2A showed complete absence of p16 staining. Of the 2 tumors with a hemizygous deletion of CDKN2A, 1 showed diffuse and strong p16 positivity, whereas the other showed complete absence of staining. In the p16-negative case, we did not find intragenic mutations or DNA promoter methylation to explain the p16 protein loss, implicating other mechanisms in the regulation of protein expression. In our cohort, subclonal or complete absence of p16 staining was associated with worse overall survival compared with positive p16 staining (1-year overall survival: 28.6% vs 90.7%, respectively; n = 32; P < .001), with all 7 patients in the p16-negative group having succumbed to their disease within 2 years of diagnosis. Our results suggested CDKN2A alterations as a cooperative driver of tumorigenesis in a subset of HGESSs with the YWHAE::NUTM2 gene fusion and showed p16 to be a potential prognostic marker.
Assuntos
Neoplasias do Endométrio , Sarcoma do Estroma Endometrial , Sarcoma , Feminino , Humanos , Neoplasias do Endométrio/patologia , Prognóstico , Hibridização in Situ Fluorescente , Sarcoma do Estroma Endometrial/genética , Sarcoma do Estroma Endometrial/patologia , Homozigoto , Deleção de Sequência , Sarcoma/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Fusão Gênica , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismoRESUMO
PURPOSE: The unique chromosomal rearrangements of endometrial stromal sarcoma (ESS) make it possible to distinguish high-grade ESS (HGESS) and low-grade ESS (LGESS) from the molecular perspective. Analysis of ESS at the genomic and transcriptomic levels can help us achieve accurate diagnosis of ESS and provide potential therapy options for ESS patients. Materials and Methods: A total of 36 ESS patients who conducted DNA- and/or RNA-based next-generation sequencing were retrospectively enrolled in this study. The molecular characteristics of ESS at genomic and transcriptomic levels, including mutational spectrum, fusion profiles, gene expression and pathway enrichment analysis and features about immune microenvironment were comprehensively explored. RESULTS: TP53 and DNMT3A mutations were the most frequent mutations. The classical fusions frequently found in HGESS (ZC3H7B-BCOR and NUTM2B-YWHAE) and LGESS (JAZF1-SUZ12) were detected in our cohort. CCND1 was significantly up-regulated in HGESS, while the expression of GPER1 and PGR encoding estrogen receptor (ER) and progesterone receptor (PR) did not differ significantly between HGESS and LGESS. Actionable mutations enriched in homologous recombination repair, cell cycle, and phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathways were detected in 60% of HGESS patients. Genes with up-regulated expression in HGESS were significantly enriched in five immune-related pathways. Most HGESS patients (85.7%) had positive predictors of immunotherapy efficacy. Moreover, immune microenvironment analysis showed that HGESS had relatively high immune infiltration. The degree of immune infiltration in HGESS patients with ZC3H7B-BCOR fusion was relatively higher than that of those with NUTM2B-YWHAE fusion. CONCLUSION: This study investigated the molecular characteristics of ESS patients at the genomic and transcriptomic levels and revealed the potentially high sensitivity of targeted therapy and immunotherapy in a subset of HGESS with specific molecular features, providing a basis for guiding decision-making of treatment and the design of future clinical trials on precision therapy.
Assuntos
Neoplasias do Endométrio , Sarcoma do Estroma Endometrial , Feminino , Humanos , Sarcoma do Estroma Endometrial/genética , Sarcoma do Estroma Endometrial/terapia , Sarcoma do Estroma Endometrial/diagnóstico , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Transcriptoma , Estudos Retrospectivos , Fosfatidilinositol 3-Quinases/metabolismo , Fatores de Transcrição/genética , Genômica , Imunoterapia , Microambiente Tumoral/genéticaRESUMO
Endometrial stromal tumors (EST) are uterine mesenchymal tumors, which histologically resemble endometrial stroma of the functioning endometrium. The majority of EST are malignant tumors classified as low-grade endometrial stromal sarcoma (LG-ESS), high-grade endometrial stromal sarcoma (HG-ESS), and undifferentiated uterine sarcoma (UUS). Overall, ESTs are rare malignancies, with an annual incidence of approximately 0.30 per 100'000 women, mainly affecting peri- or postmenopausal women. The most common genetic alteration identified in LG-ESS is the JAZF1-SUZ12 rearrangement, while t(10;17)(q23,p13) translocation and BCOR gene abnormalities characterize two major subtypes of HG-ESS. The absence of specific genetic abnormalities is the actual hallmark of UUS. Unlike HG-ESSs, LG-ESSs usually express estrogen and progesterone receptors. Total hysterectomy without morcellation and bilateral salpingo-oophorectomy (BSO) is the first-line treatment of early-stage LG-ESS. Ovarian preservation, fertility-sparing treatment, and adjuvant hormonal therapy ± radiotherapy may be an option in selected cases. In advanced or recurrent LG-ESS, surgical cytoreduction followed by hormonal treatment, or vice versa, are acceptable treatments. The standard treatment for apparently early-stage HG-ESS and UUS is total hysterectomy without morcellation with BSO. Ovarian preservation and adjuvant chemotherapy ± radiotherapy may be an option. In advanced or recurrent HG-ESS, surgical cytoreduction and neoadjuvant or adjuvant chemotherapy can be considered. Alternative treatments, including biological agents and immunotherapy, are under investigation. LG-ESSs are indolent tumor with a 5-year overall survival (OS) of 80-100% and present as stage I-II at diagnosis in two third of patients. HG-ESSs carry a poor prognosis, with a median OS ranging from 11 to 24 months, and 70% of patients are in stage III-IV at presentation. UUS median OS ranges from 12 to 23 months and, at diagnosis, 70% of patients are in stage III-IV. The aim of this review is to assess the clinical, pathological, and biological features and the therapeutic options for malignant ESTs.
Assuntos
Neoplasias do Endométrio , Tumores do Estroma Endometrial , Sarcoma do Estroma Endometrial , Humanos , Feminino , Tumores do Estroma Endometrial/epidemiologia , Tumores do Estroma Endometrial/genética , Tumores do Estroma Endometrial/terapia , Sarcoma do Estroma Endometrial/epidemiologia , Sarcoma do Estroma Endometrial/genética , Sarcoma do Estroma Endometrial/terapia , Neoplasias do Endométrio/epidemiologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/terapia , Útero/patologia , Endométrio/patologiaRESUMO
Endometrial stromal sarcomas (ESS) are morphologically and molecularly heterogeneous. We report novel gene fusions (EPC1::EED, EPC1::EZH2, ING3::PHF1) identified by targeted RNA sequencing in five cases. The ING3::PHF1-fusion positive ESS presented in a 58-year-old female as extrauterine mesocolonic, ovarian masses, and displayed large, monomorphic ovoid-to-epithelioid cells arranged in solid sheets. The patient remained alive with disease 13 months after surgery. The three ESS with EPC1::EED occurred in the uterine corpus in patients with a median age of 58 years (range 27-62 years). One tumor showed a uniform epithelioid nested morphology, while the other two were composed of monomorphic spindle cells in fascicles with elevated mitotic figures, focal tumor cell necrosis, and lymphovascular invasion. At a median follow-up of 20 months, two patients developed local recurrence, including one with concomitant distant metastasis, while one patient remained free of disease. All three patients were alive at the last follow-up. The EPC1::EZH2-fusion positive ESS presented in a 52-year-old female in the uterus, and displayed uniform spindled cells arranged in short fascicles, with focally elevated mitotic activity but without necrosis. The patient remained free of disease 3 months after surgery. All cases were diffusely positive for CD10; four diffusely express estrogen and progesterone receptors. Our study expands the molecular spectrum of EPC1 and PHF1-related gene fusions in ESS to include additional novel subunits of the PRC2 and/or NuA4/TIP60 complexes. These cases displayed a monomorphic epithelioid or spindled phenotype, spanning low-grade and high-grade cytomorphology, all expressing CD10 and commonly ER and PR, and are prone to local and/or distant spread.
Assuntos
Neoplasias do Endométrio , Sarcoma do Estroma Endometrial , Feminino , Humanos , Sarcoma do Estroma Endometrial/genética , Sarcoma do Estroma Endometrial/cirurgia , Sarcoma do Estroma Endometrial/patologia , Montagem e Desmontagem da Cromatina , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/cirurgia , Neoplasias do Endométrio/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fusão Gênica , Proteínas de Homeodomínio/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
We report an exceptional case of an undifferentiated round and spindle cell sarcoma, occurring in the periprostatic region of a 54-year-old male, with a 'high-grade endometrial stromal sarcoma-like' (HG-ESS) morphology and harboring a ZC3H7B::BCOR gene fusion identified by RNA-based next-generation sequencing. In this report, we describe the striking overlap of morphologic, immunohistochemical and molecular features of this current case and previously reported similar cases with ZC3H7B::BCOR fusion-positive HG-ESS, and discuss the differential diagnosis and possible pathogenesis of this unusual entity.
Assuntos
Neoplasias do Endométrio , Sarcoma do Estroma Endometrial , Sarcoma , Feminino , Masculino , Humanos , Pessoa de Meia-Idade , Neoplasias do Endométrio/patologia , Sarcoma do Estroma Endometrial/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Sarcoma/diagnóstico , Sarcoma/genéticaRESUMO
MEIS1::NCOA1/2 sarcomas are a newly recognized group of exceedingly rare low-grade spindle cell sarcomas that often involve the genitourinary and gynecologic tracts. Due to its deceptively low-grade morphology and the non-specific immunoprofile, these neoplasms may pose a diagnostic challenge by histologically mimicking other entities such as endometrial stromal sarcoma, smooth muscle tumor, or uterine perivascular epithelioid cell tumor (PEComa). Histologically, MEIS1::NCOA1/2 sarcomas typically show spindle cell proliferation with hyperchromatic nuclei and a generalized cytologic uniformity, arranged in short fascicles and exhibiting alternating zones of hypo- and hypercellularity. Among the previously reported cases, molecular analysis revealed the MEIS1::NCOA2 fusion as the most commonly detected fusion gene, whereas the MEIS1::NCOA1 fusion gene has been reported in only a single case that involved kidney. Herein we report the first case of uterine sarcoma harboring the MEIS1::NCOA1 fusion gene that was initially misclassified as low-grade endometrial stromal sarcoma, demonstrating its clinicopathologic features, and highlighting the essential role of molecular pathology to arrive at the accurate diagnosis that may alter disease classification and inform therapy.
Assuntos
Neoplasias do Endométrio , Sarcoma do Estroma Endometrial , Neoplasias Uterinas , Humanos , Feminino , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Sarcoma do Estroma Endometrial/diagnóstico , Sarcoma do Estroma Endometrial/genética , Sarcoma do Estroma Endometrial/patologia , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética , Útero/patologia , Coativador 1 de Receptor Nuclear/genéticaRESUMO
Introduction. High-grade endometrial stromal sarcomas (HGESS) are rare malignant mesenchymal tumors of the uterus with aggressive poor clinical outcome, which frequently exhibit YWHAE::NUTM2 and ZC3H7B::BCOR fusions. In this study, we aimed to investigate HGESSs with YWHAE and BCOR translocations through our archive materials, and to identify morphological, immunohistochemical and molecular features of these tumors. We also assessed the diagnostic value of BCOR immunohistochemistry (IHC) in HGESSs, low-grade endometrial stromal sarcomas (LGESS) and uterine leiomyosarcomas. Methods. One hundred fifty-one uterine sarcomas diagnosed between 2000-2019 were reevaluated, and tumors of 39 patients with specific features were included in the study. Fluorescence in situ hybridization (FISH) studies using YWHAE and BCOR break-apart probes and BCOR IHC were performed. BCOR IHC was also performed in 20 leiomyosarcomas and 19 LGESSs. Results. In six HGESSs, translocations involving YWHAE or BCOR were detected. Five tumors showed high-grade morphology and revealed YWHAE translocation. One HGESS with myxoid morphology revealed BCOR translocation. In immunohistochemistry, three (3/4) YWHAE translocated HGESSs showed BCOR expression. However, the BCOR translocated HGESS was BCOR negative. The study showed that all LGESSs were immunohistochemically negative with BCOR. Although 15% (3/20) leiomyosarcomas reveal focal weak-moderate BCOR expression. Conclusion. BCOR IHC is a useful marker to distinguish LGESS from HGESS. A small percentage of uterine leiomyosarcomas reveal BCOR expression; however, it is not as diffuse and strong as in HGESSs. Strong and diffuse BCOR IHC expression is highly suggestive for HGESS. The diagnosis of HGESS should be supported by molecular studies such as FISH.
Assuntos
Neoplasias do Endométrio , Leiomiossarcoma , Sarcoma do Estroma Endometrial , Sarcoma , Neoplasias Uterinas , Feminino , Humanos , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Sarcoma do Estroma Endometrial/diagnóstico , Sarcoma do Estroma Endometrial/genética , Hibridização in Situ Fluorescente , Imuno-Histoquímica , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética , Translocação GenéticaRESUMO
The landscape of uterine sarcomas is becoming increasingly complex with the description of new entities associated with recurrent molecular alterations. Uterine sarcomas, as well as soft tissue sarcomas, can be distinguished into complex genomic sarcomas and simple genomic sarcomas. Leiomyosarcoma and pleomorphic type undifferentiated uterine sarcoma belong to the first group. Low-grade and high-grade endometrial stromal sarcomas, NTRK, COL1A1::PDGFB, ALK, RET, ROS1 associated sarcomas, and SMARCA4 deficient uterine sarcoma belong to the second group. Leiomyosarcoma is the most common uterine sarcoma followed by endometrial stromal sarcomas. Three different histologic subtypes of leiomyosarcomas are recognized with distinct diagnostic criteria and different clinical outcomes, the myxoid and epithelioid leiomyosarcomas being even more aggressive than the fusiform type. The distinction between low-grade and high-grade endometrial stromal sarcoma is based first on morphology and immunohistochemistry. The detection of fusion transcripts helps in the diagnosis. Definitely recognized as a separate entity, uterine PEComa is a rare tumor whose diagnostic criteria are being recently defined. Uterine PEComa has a specific algorithm stratifying the tumors into uncertain malignant potential and malignant tumors. Embryonal rhabdomyosarcomas of the uterine cervix are not restricted to children but can also be observed in adult women and are almost always DICER1 mutated, unlike embryonal rhabdomyosarcoma of the vagina which are DICER1wild-type, and adenosarcoma which can be DICER1 mutated but with less frequency. As sarcomas associated with fusion transcripts involving the NTRK, ALK, COL1A1::PDGFB genes can benefit from targeted therapy, systematic detection are now relevant especially for patients with high risk of relapse or in recurrent setting. The integration of molecular data with dedicated expert pathology review for histology and clinical data allows better identification of uterine sarcomas in order to better treat them.