Other Uterine Sarcomas
01 Jan 2013-pp 289-299
TL;DR: The three nonleiomyosarcoma tumors, (low-grade) endometrial stromal sarcoma, high-grade undifferentiated stroma, and mixed Mullerian tumors including carcinosarcomA are all very different from one another biologically.
Abstract: Beyond leiomyosarcoma, uterine sarcomas and tumors that contain “sarcoma” in the name (ie, carcinosarcoma) are well-recognized biological entities The three nonleiomyosarcoma tumors, (low-grade) endometrial stromal sarcoma, high-grade undifferentiated stromal sarcoma, and mixed Mullerian tumors including carcinosarcoma, are all very different from one another biologically They are often omitted in discussions of soft tissue pathology as different groups of pathologists generally review such cases in expert centers than those who review soft tissue or bone tumors Age distribution for adult uterine endometrial stromal tumors is shown in Fig 211
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01 Jan 2012
TL;DR: In this article, the role of EMT and chromosomal aberrations in Uterine Carcinosarcoma (CS) tumor formation was examined by Gene Set Enrichment Analysis (GSEA), Fisher's exact test, and clustering using intrinsic gene set.
Abstract: Uterine carcinosarcoma (CS) is usually classified as uterine endometrial carcinoma (EC). However, CS is more aggressive even compared with high grade EC. CS is also reported to undergo epithelial to mesenchymal transition (EMT). In this study, we compared the gene expression profiles of CS, EC, and uterine sarcoma (US) and evaluated the role of EMT and chromosomal aberrations in CS tumor formation. Frozen tissues of 46 patients (14 CS, 24 EC, and 8 US) were included. The similarity was examined by Gene Set Enrichment Analysis (GSEA), Fisher's exact test, and clustering using “intrinsic gene set”. We examined the expression of 39 EMT‐related genes and evaluated TGF‐beta signaling by phospho‐SMAD2/3 (p‐SMAD2/3) staining. Chromosomal regions differing between CS and EC were identified by chromosomal GSEA and comparative genomic hybridization (CGH) microarrays. Three statistical methods confirmed that CS resembled US rather than EC. Acquired markers of EMT were upregulated and attenuated markers of EMT were downregulated in CS. Immunohistochemistry showed that carcinomatous region of CS have higher expression of p‐SMAD2/3 than EC (P = 0.008). Chromosomal GSEA showed that genes located at 19q13 had higher expression in CS. Furthermore, CGH microarray indicated that the TGFB1 locus at 19q13.1 was amplified in 4 of 7 samples. Based on the expression profile, CS resembles US rather than EC. TGF‐beta signaling is activated in CS and chromosomal gains at 19q13, which includes the TGFB1 locus, suggest that this may contribute to high expression of TGF‐beta and thereby EMT phenotype of CS. © 2011 Wiley Periodicals, Inc.
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TL;DR: Prognostic factor analysis shows that stage, age and histological subtype were important predictors of behaviour which may explain differences between CS and LMS, and CS appears to show more kinship to poorly differentiated endometrial carcinomas in behaviour.
449 citations
TL;DR: It is suggested that the less malignant endometrial stromal tumors may evolve toward more malignant types, but that someendometrialStromal sarcomas with relatively abundant mitotic activity may compose a biologically distinct group.
Abstract: Endometrial stromal tumors are divided into three types: benign stromal nodules, endometrial stromal sarcomas, and undifferentiated endometrial sarcomas. A variety of cytogenetic abnormalities involving chromosome 7 have been reported in endometrial stromal sarcomas, including a recurrent t(7;17)(p15;q21). We have identified two zinc finger genes, which we have termed JAZF1 and JJAZ1, at the sites of the 7p15 and 17q21 breakpoints. Analyses of tumor RNA indicate that a JAZF1/JJAZ1 fusion is present in all types of endometrial stromal tumors; however, the fusion appears to be rarer among endometrial stromal sarcomas that would be considered high-grade according to certain classification schemes. These findings suggest that the less malignant endometrial stromal tumors may evolve toward more malignant types, but that some endometrial stromal sarcomas with relatively abundant mitotic activity may compose a biologically distinct group.
359 citations
TL;DR: Tumors with YWHAE-FAM22 rearrangements constitute a distinct group of ESS, which is associated with high-grade morphology and aggressive clinical behavior compared to JAZF1 ESS.
Abstract: Endometrial stromal sarcoma (ESS) is a genetically heterogenous group of uterine sarcomas, of which almost half are associated with JAZF1 rearrangement. We recently identified a novel genetic fusion between YWHAE and FAM22A/B in ESS harboring t(10;17)(q22;p13) and herein describe the clinicopathologic features of 13 YWHAE-FAM22 ESS cases (11 primary and 3 metastatic) and compare them with 20 ESS cases with JAZF1 rearrangement. Ten of 11 primary uterine tumors contained morphologically high-grade areas composed of round cells arranged in nests with a delicate stromal capillary network. The tumor cells showed large nuclei with irregular nuclear contours and significant mitotic activity (>10 mitoses/10 HPF) in addition to focal tumor necrosis, in contrast to JAZF1 ESS, which lacked a nested growth pattern, were composed of cells with small round/oval nuclei, and typically had <5 MF/10 HPF. In 7 of the 11 uterine tumors, there was an additional cytologically bland and mitotically weakly active spindle cell component with a fibrous/fibromyxoid stroma (ESS, fibromyxoid variant). Two metastatic tumors (pulmonary) also contained round cell and spindle cell components, whereas 1 metastasis (vaginal) was composed solely of the spindle cell component. In both primary and metastatic tumors, the spindle cells were diffusely positive for estrogen and progesterone receptors and CD10, in contrast to the round cell areas, which were negative. Clinically, 10 of 12 patients with YWHAE-FAM22 ESS presented with FIGO stages II to III disease, in contrast to only 4 of 16 patients with JAZF1 ESS presenting with stages II to III disease (P<0.05). Tumors with YWHAE-FAM22 rearrangements constitute a distinct group of ESS, which is associated with high-grade morphology and aggressive clinical behavior compared to JAZF1 ESS. Thus, their distinction from typical JAZF1 ESS is important for prognostic and therapeutic purposes.
246 citations
TL;DR: Fluorescence in situ hybridization analysis demonstrated absolute specificity of YWHAE–FAM22A/B genetic rearrangement for high-grade ESS, with no fusions detected in other uterine and nonuterine mesenchymal tumors, which reveal diagnostically and therapeutically relevant models for characterizing aberrant 14-3-3 oncogenic functions.
Abstract: 14-3-3 proteins are ubiquitously expressed regulators of various cellular functions, including proliferation, metabolism, and differentiation, and altered 14-3-3 expression is associated with development andprogressionof cancer. Wereport a transforming14-3-3 oncoprotein, which we identified through conventional cytogenetics and whole-transcriptome sequencing analysis as a highly recurrent genetic mechanism in a clinically aggressive form of uterine sarcoma: high-grade endometrial stromal sarcoma (ESS). The 14-3-3 oncoproteinresultsfromat(10;17) genomicrearrangement,leadingtofusion between 14-3-3e (YWHAE) and either of two nearly identical FAM22 family members (FAM22A or FAM22B). Expression of YWHAE– FAM22 fusion oncoproteins was demonstrated by immunoblot in t (10;17)-bearing frozen tumor and cell line samples. YWHAE–FAM22 fusion gene knockdowns were performed with shRNAs and siRNAs targeting various FAM22A exons in an t(10;17)-bearing ESS cell line (ESS1): Fusion protein expression was inhibited, with corresponding reduction in cell growth and migration. YWHAE–FAM22 maintains a structurally and functionally intact 14-3-3e (YWHAE) protein-binding domain, which is directed to the nucleus by a FAM22 nuclear localization sequence. In contrast to classic ESS, harboring JAZF1 genetic fusions, YWHAE–FAM22 ESS display high-grade histologic features, a distinct gene-expression profile, and a more aggressive clinical course. Fluorescence in situ hybridization analysis demonstrated absolute specificity of YWHAE–FAM22A/B genetic rearrangement for high-grade ESS, with no fusions detected in other uterine and nonuterine mesenchymal tumors (55 tumor types, n =8 27). These discoveries reveal diagnostically and therapeutically relevant models for characterizing aberrant 14-3-3 oncogenic functions. cytogenetic aberration | translocation | uterine neoplasm | NUT | leiomyosarcoma
231 citations
TL;DR: Comparing patient outcome following treatment with adjuvant whole abdominal irradiation versus (vs.) chemotherapy for patients with uterine carcinosarcoma did not find a statistically significant advantage in recurrence rate or survival, but the observed differences favor the use of combination chemotherapy in future trials.
229 citations