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。
