Abstract:
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.
摘要:
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。