Homeobox Protein Nkx-2.2

Homeobox 蛋白 Nkx - 2.2
  • 文章类型: Journal Article
    年轻人的成熟型糖尿病(MODY)代表了单基因糖尿病(DM)的最常见形式,目前根据参与胰腺β细胞分化和功能的单基因突变分为14种不同的亚型。很大一部分MODY的病因不明,这表明遗传景观仍有待探索。最近,新的潜在MODY因果基因,参与β细胞的分化和功能,已经被确认,如RFX6,NKX2.2,NKX6.1,WFS1,PCBD1,MTOR,TBC1D4,CACNA1E,MNX1,AKT2,NEUROG3,EIF2AK3,GLIS3,HADH,PTF1A。MODY变异的遗传和临床特征仍然高度异质性,没有直接的基因型-表型相关性,尤其是低渗透剂亚型。这是对文献的叙述性回顾,旨在描述与MODY相关的新颖变体的最新技术。为了更深入地了解MODY的复杂性,我们还报道了一些关于一些众所周知的病理基因和MODY遗传模式的病因学作用的相关争议,以及MODY与自身免疫性糖尿病的罕见关联。由于可用数据有限,MODY相关基因的致病性评估仍然具有挑战性,特别是在稀有和低渗透亚型的背景下。考虑到准确诊断的重要性,MODY的预后和管理,需要更多的研究来进一步研究其遗传景观和基因型-表型相关性,以及非遗传修饰因子在这一组患者中的致病作用。
    Maturity-onset diabetes of the young (MODY) represents the most frequent form of monogenic diabetes mellitus (DM), currently classified in 14 distinct subtypes according to single gene mutations involved in the differentiation and function of pancreatic β-cells. A significant proportion of MODY has unknown etiology, suggesting that the genetic landscape is still to be explored. Recently, novel potentially MODY-causal genes, involved in the differentiation and function of β-cells, have been identified, such as RFX6, NKX2.2, NKX6.1, WFS1, PCBD1, MTOR, TBC1D4, CACNA1E, MNX1, AKT2, NEUROG3, EIF2AK3, GLIS3, HADH, and PTF1A. Genetic and clinical features of MODY variants remain highly heterogeneous, with no direct genotype-phenotype correlation, especially in the low-penetrant subtypes. This is a narrative review of the literature aimed at describing the current state-of-the-art of the novel likely MODY-associated variants. For a deeper understanding of MODY complexity, we also report some related controversies concerning the etiological role of some of the well-known pathological genes and MODY inheritance pattern, as well as the rare association of MODY with autoimmune diabetes. Due to the limited data available, the assessment of MODY-related genes pathogenicity remains challenging, especially in the setting of rare and low-penetrant subtypes. In consideration of the crucial importance of an accurate diagnosis, prognosis and management of MODY, more studies are warranted to further investigate its genetic landscape and the genotype-phenotype correlation, as well as the pathogenetic contribution of the nongenetic modifiers in this cohort of patients.
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  • 文章类型: Journal Article
    除了致命的中线癌(NUT癌),NUTM1易位在间质肿瘤中也有报道,但是非常罕见。这里,我们描述了一系列8例NUTM1重排肉瘤,以进一步表征该新兴实体的临床病理特征.该队列包括2名男性和6名女性,年龄从24岁到64岁(平均值:51岁;中位数:56岁)。肿瘤发生在结肠(2),腹部(2),空肠(1),食管(1),肺(1)和眶下区域(1)。诊断时,6例患者出现转移性疾病。肿瘤大小1~10.5cm(平均6cm,中位数5.5cm)。组织学上,4个肿瘤由原始的小圆形细胞到上皮样细胞与可变梭形细胞混合组成,而3例肿瘤仅由小圆形细胞至上皮样细胞组成,1例肿瘤主要由高级梭形细胞组成。肿瘤细胞排列在固体薄片中,巢,或相交的束。有丝分裂活性范围为1至15/10HPF(中位数:5/10HPF)。其他特征包括横纹肌表型(4/8),明显的核卷积(2/8),显著的基质透明化(2/8),局灶性黏液样基质(1/8),破骨细胞病灶(1/8),坏死(1/8)。通过免疫组织化学,所有肿瘤均表现为弥漫性和强烈的NUT蛋白核染色,具有可变表达的全细胞角蛋白(AE1/AE3)(2/8),CK18(1/8),CD99(3/8),NKX2.2(2/8),周期蛋白D1(2/8),desmin(2/8),BCOR(2/8),S100(1/8),TLE1(1/8),和突触素(1/8)。8个肿瘤中有7个通过荧光原位杂交分析显示NUTM1重排。RNA测序分析确定MXD4::NUTM1(3/7),MXI1::NUTM1(3/7),和MGA::NUTM1(1/7)融合,分别。在2例病例中进行的基于DNA的甲基化分析显示出与NUT癌和未分化的小圆细胞和梭形细胞肉瘤不同的甲基化簇。随访时(范围:4到24个月),1例患者在8.5个月时复发,4例转移性疾病患者(诊断后5、10、11和24个月),3例患者保持良好状态,无复发或转移迹象(诊断后4、6和12个月)。我们的研究进一步证明,NUTM1重排肉瘤具有广泛的临床病理特征。NUT免疫组织化学应包括在单调未分化小圆的诊断方法中,上皮样至高级别梭形细胞恶性肿瘤,难以通过常规方法进行分类。基于DNA的甲基化分析可能为未分化肉瘤的表观遗传分类提供有希望的工具。
    Apart from the lethal midline carcinoma (NUT carcinoma), NUTM1 translocation has also been reported in mesenchymal tumors, but is exceedingly rare. Here, we describe a series of 8 NUTM1 -rearranged sarcomas to further characterize the clinicopathologic features of this emerging entity. This cohort included 2 males and 6 females with age ranging from 24 to 64 years (mean: 51 y; median: 56 y). Tumors occurred in the colon (2), abdomen (2), jejunum (1), esophagus (1), lung (1) and infraorbital region (1). At diagnosis, 6 patients presented with metastatic disease. Tumor size ranged from 1 to 10.5 cm (mean: 6 cm; median: 5.5 cm). Histologically, 4 tumors were composed of primitive small round cells to epithelioid cells intermixed with variable spindle cells, while 3 tumors consisted exclusively of small round cells to epithelioid cells and 1 tumor consisted predominantly of high-grade spindle cells. The neoplastic cells were arranged in solid sheets, nests, or intersecting fascicles. Mitotic activity ranged from 1 to 15/10 HPF (median: 5/10 HPF). Other features included rhabdoid phenotype (4/8), pronounced nuclear convolutions (2/8), prominent stromal hyalinization (2/8), focally myxoid stroma (1/8), foci of osteoclasts (1/8), and necrosis (1/8). By immunohistochemistry, all tumors showed diffuse and strong nuclear staining of NUT protein, with variable expression of pancytokeratin (AE1/AE3) (2/8), CK18 (1/8), CD99 (3/8), NKX2.2 (2/8), cyclin D1 (2/8), desmin (2/8), BCOR (2/8), S100 (1/8), TLE1 (1/8), and synaptophysin (1/8). Seven of 8 tumors demonstrated NUTM1 rearrangement by fluorescence in situ hybridization analysis. RNA-sequencing analysis identified MXD4::NUTM1 (3/7), MXI1::NUTM1 (3/7), and MGA::NUTM1 (1/7) fusions, respectively. DNA-based methylation profiling performed in 2 cases revealed distinct methylation cluster differing from those of NUT carcinoma and undifferentiated small round cell and spindle cell sarcomas. At follow-up (range: 4 to 24 mo), 1 patient experienced recurrence at 8.5 months, 4 patients were alive with metastatic disease (5, 10, 11, and 24 mo after diagnosis), 3 patients remained well with no signs of recurrence or metastasis (4, 6, and 12 mo after diagnosis). Our study further demonstrated that NUTM1 -rearranged sarcoma had a broad range of clinicopathologic spectrum. NUT immunohistochemistry should be included in the diagnostic approach of monotonous undifferentiated small round, epithelioid to high-grade spindle cell malignancies that difficult to classify by conventional means. DNA-based methylation profiling might provide a promising tool in the epigenetic classification of undifferentiated sarcomas.
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  • 文章类型: Journal Article
    中枢神经系统中的快速信息处理需要少突胶质细胞对轴突进行髓鞘化。转录因子Sox2及其紧密相关Sox3冗余地调节髓鞘形成少突胶质细胞的发育,但是对潜在的分子机制知之甚少。这里,我们表征了早期分化过程中培养的少突胶质细胞的表达谱,并将Bcas1,Enpp6,Zfp488和Nkx2.2鉴定为Sox2和Sox3缺失后的主要下调基因。对Sox2和Sox3的少突胶质细胞特异性缺失的小鼠的分析验证了所有四个基因作为体内下游靶标。另外的功能测定鉴定了每个基因附近的调节区,其响应并结合两种Sox蛋白。因此,Bcas1、Enpp6、Zfp488和Nkx2.2可能代表Sox2和Sox3的直接靶基因和主要效应子。考虑到这些基因在前髓鞘少突胶质细胞中的优先表达和作用,我们的研究结果表明,Sox2和Sox3在前髓鞘形成阶段影响少突胶质细胞的发育,Bcas1,Enpp6,Zfp488和Nkx2.2是它们的主要效应因子.
    Rapid information processing in the central nervous system requires the myelination of axons by oligodendrocytes. The transcription factor Sox2 and its close relative Sox3 redundantly regulate the development of myelin-forming oligodendrocytes, but little is known about the underlying molecular mechanisms. Here, we characterized the expression profile of cultured oligodendroglial cells during early differentiation and identified Bcas1, Enpp6, Zfp488 and Nkx2.2 as major downregulated genes upon Sox2 and Sox3 deletion. An analysis of mice with oligodendrocyte-specific deletion of Sox2 and Sox3 validated all four genes as downstream targets in vivo. Additional functional assays identified regulatory regions in the vicinity of each gene that are responsive to and bind both Sox proteins. Bcas1, Enpp6, Zfp488 and Nkx2.2 therefore likely represent direct target genes and major effectors of Sox2 and Sox3. Considering the preferential expression and role of these genes in premyelinating oligodendrocytes, our findings suggest that Sox2 and Sox3 impact oligodendroglial development at the premyelinating stage with Bcas1, Enpp6, Zfp488 and Nkx2.2 as their major effectors.
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  • 文章类型: Journal Article
    现在理解相同的基因融合体可以由不同的实体共享。我们报告了一种独特的皮肤和皮下组织肿瘤,携带尤因肉瘤相关的EWSR1::FLI1融合,但与尤因肉瘤不同.检索了5种编码为尤因肉瘤以外并带有EWSR1::FLI1的皮肤肿瘤的载玻片和块。从报告中提取了免疫组织化学和分子遗传学结果。进行甲基化分析。获得临床信息。肿瘤发生在4名男性和1名女性(中位年龄25岁;范围19-69岁),并涉及背部的皮肤/皮下组织(2),大腿,臀部,和胸壁(中位数2.4厘米;范围1-11cm)。在引起临床关注之前,有两个肿瘤出现了“几年”。病变是多结节的,限制。由平淡的巢组成,圆形细胞与含有梭状细胞的透明胶原带混合。经常出现出血和囊性改变;没有坏死。所有均为弥漫性S100蛋白/SOX10阳性;5个中的4个为CD99阴性。一个测试病例对NKX2呈强烈阳性。各种其他测试标志物要么是局灶性阳性(GFAP,p63)或阴性。分子遗传学结果为:EWSR1外显子7::FLI1外显子8,EWSR1外显子11::FLI1外显子5,EWSR1外显子11::FLI1外显子6,EWSR1外显子7::FLI1外显子6和EWSR1外显子10::FLI1外显子6。甲基化分析(3例)显示这些形成一个独特的簇,有别于尤因肉瘤.所有患者均行切缘阴性切除,其中1例接受1周期化疗。临床随访显示,所有患者均无疾病存活(中位数17个月;范围11-62个月)。尽管有相似的基因融合,形态学,免疫组织化学,表观遗传,这些独特的EWSR1::FLI1融合的皮肤和皮下组织肿瘤的临床特征与尤文肉瘤大不相同。有趣的是,EWSR1重排涉及外显子10或11,仅在尤因肉瘤中很少见,在大多数情况下。浅表神经EWSR1::FLI1融合肿瘤应与真正的皮肤尤因肉瘤严格区分。
    It is now understood that identical gene fusions may be shared by different entities. We report a distinctive neoplasm of the skin and subcutis, harboring the Ewing sarcoma-associated EWSR1::FLI1 fusion but differing otherwise from Ewing sarcoma. Slides and blocks for 5 cutaneous neoplasms coded as other than Ewing sarcoma and harboring EWSR1::FLI1 were retrieved. Immunohistochemical and molecular genetic results were abstracted from reports. Methylation profiling was performed. Clinical information was obtained. The tumors occurred in 4 men and 1 woman (median: 25 years of age; range: 19-69 years) and involved the skin/subcutis of the back (2), thigh, buttock, and chest wall (median: 2.4 cm; range: 1-11 cm). Two tumors were present \"years\" before coming to clinical attention. The lesions were multinodular and circumscribed and consisted of nests of bland, round cells admixed with hyalinized collagenous bands containing spindled cells. Hemorrhage and cystic change were often present; necrosis was absent. All were diffusely S100 protein/SOX10-positive; 4 of 5 were CD99-negative. One tested case was strongly positive for NKX2.2. A variety of other tested markers were either focally positive (glial fibrillary acidic protein, p63) or negative. Molecular genetic results were as follows: EWSR1 exon 7::FLI1 exon 8, EWSR1 exon 11::FLI1 exon 5, EWSR1 exon 11::FLI1 exon 6, EWSR1 exon 7::FLI1 exon 6, and EWSR1 exon 10::FLI1 exon 6. Methylation profiling (3 cases) showed these to form a unique cluster, distinct from Ewing sarcoma. All patients underwent excision with negative margins; one received 1 cycle of chemotherapy. Clinical follow-up showed all patients to be alive without disease (median: 17 months; range: 11-62 months). Despite similar gene fusions, the morphologic, immunohistochemical, epigenetic, and clinical features of these unique EWSR1::FLI1-fused neoplasms of the skin and subcutis differ substantially from Ewing sarcoma. Interestingly, EWSR1 rearrangements involved exons 10 or 11, only rarely seen in Ewing sarcoma, in a majority of cases. Superficial neurocristic EWSR1::FLI1 fusion tumors should be rigorously distinguished from true cutaneous Ewing sarcomas.
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  • 文章类型: Case Reports
    背景:CIC重排肉瘤(CRS)代表了属于尤因样肉瘤家族的未分化小圆细胞肉瘤的新实体。CRS是最常见的类型。CIC基因的融合伴侣包括DUX4,FOXO4和最近识别的NUTM1。最近有报道称,儿科患者中罕见的CIC::NUTM1肉瘤发生在大脑中,肾,骨头,和软组织。然而,这种情况尚未在四肢的软组织中发现。
    方法:我们报告了一例位于一名18岁男性右上肢的CIC::NUTM1肉瘤。肿瘤表现出CIC::DUX4肉瘤的典型形态特征,小到中等大小的圆形细胞,小叶图案,局灶性纺锤体,粘液样基质,和斑片状坏死。肿瘤弥漫性表达NUTM1,在弱至中等强度时WT1cter呈阳性,CD99呈局部阳性,而角蛋白呈阴性,EMA,P40,MyoD1,肌原蛋白,NKX2.2,BCOR,和泛TRK。荧光原位杂交分析显示CIC和NUTM1基因裂解。
    结论:CIC::NUTM1肉瘤代表了一种新的CRS分子变异,对中枢神经系统和较年轻的儿科患者具有偏好。其形态和表型可能被误认为是NUT癌,行为比其他形式的CRS更进步。对于这种罕见的新发现的基因融合变体,在未分化肿瘤的诊断中,有必要将分子和免疫组织化学结果与形态学特征相结合。
    BACKGROUND: CIC-rearranged sarcomas (CRS) represent a new entity of undifferentiated small round cell sarcoma belonging to the Ewing-like sarcomas family. CRS are the most common type. Fusion partners for the CIC gene include DUX4, FOXO4, and the recently recognizedNUTM1. Rare cases of CIC::NUTM1 sarcoma in pediatric patients have recently been reported in brain, kidney, bone, and soft tissues. However, such cases have not been identified in the soft tissues of the limbs.
    METHODS: We reported a case of CIC::NUTM1 sarcoma located in the right upper limb of an 18-year-old man. The tumor displayed morphologic features typical of CIC::DUX4 sarcomas, with small- to medium-sized round cells, a lobular pattern, focal spindling, myxoid stroma, and patchy necrosis. The tumor diffusely expressed NUTM1, was positive for WT1cter at weak to moderate intensity, and was focally positive for CD99, while it was negative for keratins, EMA, P40, MyoD1, myogenin, NKX2.2, BCOR, and pan-TRK. Fluorescence in situ hybridization analyses revealed cleavage of the CIC and NUTM1 genes.
    CONCLUSIONS: CIC::NUTM1 sarcomas represent a novel molecular variant of CRS with a preference for the central nervous system and younger pediatric persons. Its morphology and phenotype may be mistaken for NUT carcinomas, and the behavior is more progressive than other forms of CRS. For this rare and newly discovered gene fusion variant, it is necessary to integrate molecular and immunohistochemical findings with morphologic features in the diagnosis of undifferentiated neoplasms.
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  • 文章类型: Case Reports
    一名60多岁的女性出现左侧乳房肿块。核心针活检标本显示圆形细胞肿瘤的弥漫性增殖,波形蛋白呈阳性,NKX2.2,BCOR,和免疫组织化学(IHC)上的局灶性CD99。未检测到尤因家族肉瘤的融合基因。初步诊断为原发性乳腺肉瘤(PBS),化疗后进行全乳房切除术.切除的组织显示圆形或纺锤形肿瘤细胞增殖,核质比高,表现出固体和束状排列,但没有上皮成分或类器官模式。虽然IHC没有特别的组织学诊断,基因组检查显示MED12p.G44D中的基因改变,MLL2(KMT2D)p.T1496fs*27和EGFR变体III(vIII)。此外,一项回顾性IHC研究显示EGFRvIII过表达.恶性叶状肿瘤(PT)伴广泛的肉瘤过度生长被认为是综合诊断。这是罕见的携带EGFRvIII的恶性PT病例。本病例提供了准确诊断和基因组分析罕见乳腺肿瘤的重要性,由于恶性PT和PBS在其治疗策略和预后方面存在差异。
    A female in her 60\'s presented with a left-sided breast mass. A core needle biopsy specimen showed diffuse proliferation of a round cell tumor, which was positive for vimentin, NKX2.2, BCOR, and focal CD99 on immunohistochemistry (IHC). No fusion genes of the Ewing family sarcomas were detected. With a tentative diagnosis of primary breast sarcoma (PBS), total mastectomy was performed after chemotherapy. The resected tissues showed proliferation of round or spindle-shaped tumor cells with a high nuclear-to-cytoplasmic ratio, exhibiting solid and fascicular arrangements but no epithelial component or organoid pattern. While IHC indicated no particular histological diagnosis, genomic examination revealed gene alterations in MED12 p.G44D, MLL2 (KMT2D) p.T1496fs*27, and EGFR variant III (vIII). Moreover, a retrospective IHC study showed overexpression of EGFRvIII. A malignant phyllodes tumor (PT) with extensive sarcomatous overgrowth was indicated as an integrative diagnosis. This is a rare case of a malignant PT harboring EGFRvIII. The present case provides an importance of accurate diagnosis and genomic analysis of rare breast tumors, as malignant PT and PBS are different in its treatment strategy and prognosis.
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  • 文章类型: Journal Article
    目的:本研究旨在研究具有NK同源异型盒结构域的转录因子Nkx1-2的作用,在脂肪生产的调节中。
    方法:使用定量实时聚合酶链反应或转录组测序分析基因表达。CRISPR/Cas9技术用于产生nkx1.2敲除斑马鱼和nkx1.2缺失的3T3-L1细胞。使用尼罗河红染色对斑马鱼幼虫中的脂滴产生进行视觉定量,而3T3-L1细胞中的脂滴被油红O染色。通过电泳迁移率变化实验验证了Nkx1-2与启动子的结合。
    结果:Nkx1-2在斑马鱼脂肪生产的调节中起着至关重要的作用。在斑马鱼中敲除nkx1.2会导致体重减轻,伴随着脂滴的产生显着减少,内脏和肝脏脂肪含量降低。此外,与脂质生物合成相关的基因显著下调。在3T3-L1前脂肪细胞中,Nkx1-2通过与cebpa启动子结合诱导分化为成熟脂肪细胞,从而激活其转录。此外,nkx1.2的表达受p38MAPK调控,JNK,或Smad2/3信号通路在3T3-L1细胞。
    结论:我们的研究结果表明,Nkx1-2作为脂肪产生的正调节因子,在脂肪细胞分化和脂质生物合成中起关键作用。
    This study aimed to investigate the role of Nkx1-2, a transcription factor with the NK homeobox domain, in the regulation of fat production.
    Gene expression was analyzed using quantitative real-time polymerase chain reaction or transcriptome sequencing. CRISPR/Cas9 technology was employed to generate nkx1.2 knockout zebrafish and nkx1.2-deleted 3T3-L1 cells. Lipid droplet production in zebrafish larvae was visually quantified using Nile red staining, whereas lipid droplets in 3T3-L1 cells were stained with Oil red O. The binding of Nkx1-2 to the promoter was verified through an electrophoretic mobility shift assay experiment.
    Nkx1-2 plays crucial roles in the regulation of fat production in zebrafish. Knockout of nkx1.2 in zebrafish leads to weight loss, accompanied by significantly reduced lipid droplet production and decreased visceral and liver fat content. Furthermore, genes related to lipid biosynthesis are significantly downregulated. In 3T3-L1 preadipocytes, Nkx1-2 induces differentiation into mature adipocytes by binding to the cebpa promoter, thereby activating its transcription. Additionally, the expression of nkx1.2 is regulated by the p38 MAPK, JNK, or Smad2/3 signaling pathways in 3T3-L1 cells.
    Our findings suggest that Nkx1-2 functions as a positive regulator of fat production, playing a critical role in adipocyte differentiation and lipid biosynthesis.
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  • 文章类型: Case Reports
    背景:尤因肉瘤(ES)是一种侵袭性骨和软组织癌,其中大多数倾向于发生在骨骼中。子宫颈骨外尤因肉瘤(EES)极为罕见。
    方法:在目前的工作中,我们报道了1例39岁的宫颈EES患者,肿瘤肿块2.5*2.1*1.8cm.根据以前的文献,我们的病例是有史以来在原发性宫颈ES中发现的最小肿瘤。病人最初是因为阴道出血来我们医院,然后妇科检查发现宫颈管和部分宫颈外孔之间有肿瘤。以下证实了EES的诊断:苏木精和伊红染色(H&E)显示活检标本中的小圆形蓝色恶性细胞。免疫组织化学(IHC)显示CD99、NKX2.2和FLI1的阳性染色。通过荧光原位杂交(FISH)发现EWSR1基因的破坏,并通过下一代测序(NGS)确定EWSR1-FLI1基因融合。患者接受腹腔镜广泛子宫切除术,双侧附件切除术,盆腔淋巴结清扫术,和术后辅助化疗,并保持无病定期随访1年。
    结论:通过对先前报道的宫颈ES和该病例的系统评价,我们强调了FISH和NGS对ESS诊断准确性的重要性,这可以帮助优化治疗策略。然而,由于罕见的疾病,没有标准的治疗方案。宫颈ES的分子病理诊断和治疗方案的标准化对患者的预后至关重要。
    BACKGROUND: Ewing\'s sarcoma (ES) is an aggressive cancer of bone and soft tissue, most of which tend to occur in the bone. Extraosseous Ewing\'s sarcoma (EES) of the cervix is extremely rare.
    METHODS: In the present work, we reported a 39-year-old cervical EES patient with a 2.5*2.1*1.8 cm tumor mass. According to previous literatures, our case is the smallest tumor found in primary cervical ES ever. The patient initially came to our hospital due to vaginal bleeding, and then the gynecological examination found a neoplasm between the cervical canal and partially in the external cervical orifice. The diagnosis of EES was confirmed below: Hematoxylin & Eosin staining (H&E) revealed small round blue malignant cells in biopsy specimens. Immunohistochemistry (IHC) showed the positive staining for CD99, NKX2.2, and FLI1. Disruption of EWSR1 gene was found by fluorescence in situ hybridization (FISH), and the EWSR1-FLI1 gene fusion was determined by next-generation sequencing (NGS). The patient received laparoscopic wide hysterectomy, bilateral adnexectomy, pelvic lymphadenectomy, and postoperative adjuvant chemotherapy and remained disease free with regular follow-up for 1 year.
    CONCLUSIONS: Through a systematic review of previously reported cervical ES and this case, we highlighted the importance of FISH and NGS for the accuracy of ESS diagnosis, which could assist on the optimal treatment strategy. However, due to the rarity of the disease, there is no standard treatment schemes. Investigation on molecular pathological diagnosis and standardization of treatment regimens for cervical ES are critical to patients\' prognosis.
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  • 文章类型: Journal Article
    腹膜后尤因肉瘤(RES)非常罕见,主要在病例报告中描述。这项研究的目的是回顾性分析临床病理,分子特征,生物学行为,免疫组织化学染色13例原发性RES的治疗信息,荧光原位杂交,RT-PCR和NGS测序检测技巧。13名患者包括8名男性和5名女性,平均年龄为34岁。形态学上,肿瘤由小的圆形或上皮样细胞组成,细胞质呈空泡状(6/13,46%),呈弥漫性排列,嵌套(8/13,62%)和血管周围(7/13,54%)模式。不寻常的形态模式,如脑膜瘤样漩涡结构和筛状结构是相对新颖的发现。免疫组织化学研究显示CD99(12/13;92%),CD56(11/13;85%),NKX2.2(9/13;69%),PAX7(10/11;91%)和CD117(6/9;67%)阳性。12例(92%)显示EWSR1重排,3例显示EWSR1::FLI1融合。ERCC4剪接位点变异体,一种新的致病变种,首次通过RNA测序发现。中位随访时间为14个月(6至79个月),8/13(62%)患者死亡,而5/13(38%)存活。三例复发,5例发生肝转移(2例),肺(2例)和骨(1例)。RES是一个侵略性的,高级别肿瘤,容易多次复发和转移,具有独特的形态,免疫组织化学,和分子遗传特征。ERCC4剪接突变,这是首次发现的一种新的致病变异,对了解这种疾病可能有意义,以及靶向药物的开发。
    Retroperitoneal Ewing sarcomas (RES) are very rare and mostly described in case reports. The purpose of this study was to retrospectively analyze the clinicopathology, molecular characteristics, biological behavior, and therapeutic information of 13 cases of primary RES with immunohistochemical staining, fluorescence in situ hybridization, RT-PCR and NGS sequencing detection techniques. The thirteen patients included eight males and five females with a mean age of 34 years. Morphologically, the tumors were comprised of small round or epithelial-like cells with vacuolated cytoplasm (6/13,46 %) arranged in diffuse, nested (8/13,62 %) and perivascular (7/13,54 %) patterns. Unusual morphologic patterns, such as meningioma-like swirling structures and sieve-like structures were relatively novel findings. Immunohistochemical studies showed CD99 (12/13; 92 %), CD56 (11/13; 85 %), NKX2.2 (9/13; 69 %), PAX7 (10/11;91 %) and CD117(6/9;67 %) to be positive.12 cases (92 %) demonstrated EWSR1 rearrangement and 3 cases displayed EWSR1::FLI1 fusion by FISH. ERCC4 splice-site variant, a novel pathogenic variant, was discovered for the first time via RNA sequencing. With a median follow-up duration of 14 months (6 to 79 months), 8/13 (62 %) patients died, while 5/13(38 %) survived. Three cases recurred, and five patients developed metastasis to the liver (2 cases), lung (2 cases) and bone (1 case). RES is an aggressive, high-grade tumor, prone to multiple recurrences and metastases, with distinctive morphologic, immunohistochemical, and molecular genetic features. ERCC4 splicing mutation, which is a novel pathogenic variant discovered for the first time, with possible significance for understanding the disease, as well as the development of targeted drugs.
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  • 文章类型: Journal Article
    尤文肉瘤是一种罕见的肿瘤,在与“小圆细胞”形态肿瘤的鉴别诊断中考虑,但它在妇科领域的发生仅有零星记录。在这里,我们描述了迄今为止最大的女性生殖道尤因肉瘤队列,并强调其临床病理与更常见的妇科肿瘤相似。回顾性地从5个机构中鉴定出尤文肉瘤(n=21)。患者平均年龄为35岁(6-61岁)。肿瘤部位包括子宫(n=8),子宫颈(n=4),外阴(n=5),阴道(n=1),阔韧带(n=1),腹股沟区(n=1),和骨盆(n=1)。18例幻灯片可供查阅的病例中有9例仅显示经典的圆形细胞形态,其余的显示可变的组合和突出的变体卵形/纺锤形或上皮样外观。肿瘤对CD99(20/20)表现为弥漫性膜反应性,对NKX2.2(8/8,弥漫性)和细胞周期蛋白D1(7/7,其中3/7为斑片状/多灶性,4/7为弥漫性)阳性。ER(0/6)和CD10(0/6)阴性。3例最初诊断为子宫内膜间质肉瘤。通过荧光原位杂交(n=15)和/或测序(n=8)在20/21中确认EWSR1重排。在接受测序的八个肿瘤中,6个有FLI1,1个ERG,和1FEV作为聚变伙伴。在11名获得随访的患者中,5死于疾病,1例发生肺转移,5例存活,无疾病迹象。妇科尤因肉瘤是一种罕见的,侵袭性实体,与其他更常见的妇科肿瘤具有一些形态学和免疫组织化学特征。除了典型的圆形细胞外观,也可观察到梭状/卵形至上皮样形态的变异,并应提示通过适当的免疫组织化学和/或分子研究来考虑该实体.
    Ewing sarcoma is an uncommon neoplasm considered in the differential diagnosis of tumors with \"small round cell\" morphology, but its occurrence in the gynecologic tract has only been sporadically documented. Herein, we describe the largest cohort of Ewing sarcoma localized to the female genital tract to date, and emphasize their clinicopathologic resemblance to more common gynecologic neoplasms. Ewing sarcoma (n=21) was retrospectively identified from 5 institutions. The average patient age was 35 (range 6-61) years. Tumor sites included uterus (n=8), cervix (n=4), vulva (n=5), vagina (n=1), broad ligament (n=1), inguinal area (n=1), and pelvis (n=1). Nine of 18 cases in which slides were available for review demonstrated only classic round cell morphology, with the remainder showing a variable combination and prominence of variant ovoid/spindle or epithelioid appearance. Tumors showed diffuse membranous reactivity for CD99 (20/20) and were positive for NKX2.2 (8/8, diffuse) and cyclin D1 (7/7, of which 3/7 were patchy/multifocal and 4/7 were diffuse). They were negative for ER (0/6) and CD10 (0/6). Three cases were initially diagnosed as endometrial stromal sarcomas. EWSR1 rearrangement was confirmed in 20/21 by fluorescence in situ hybridization (n=15) and/or sequencing (n=8). Of the eight tumors that underwent sequencing, 6 harbored FLI1 , 1 ERG, and 1 FEV as the fusion partner. Of 11 patients with available follow-up, 5 died of disease, 1 developed lung metastases and 5 are alive with no evidence of disease. Ewing sarcoma of the gynecologic tract is a rare, aggressive entity that shares some morphologic and immunohistochemical features with other more common gynecologic neoplasms. In addition to the typical round cell appearance, variant spindled/ovoid to epithelioid morphology may also be observed and should prompt consideration of this entity with appropriate immunohistochemical and/or molecular studies.
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