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.

中文翻译：

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扩大 NUTM1 重排肉瘤谱：8 例临床病理学和分子遗传学研究。


除了致死性中线癌（NUT 癌）外，间叶性肿瘤中也有 NUTM1 易位的报道，但极为罕见。在这里，我们描述了一系列 8 种 NUTM1 重排肉瘤，以进一步表征这一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，年龄范围为 24 至 64 岁（平均：51 岁；中位数：56 岁）。肿瘤发生在结肠（2）、腹部（2）、空肠（1）、食道（1）、肺（1）和眶下区域（1）。诊断时，6 名患者出现转移性疾病。肿瘤大小范围为 1 至 10.5 cm（平均值：6 cm；中位数：5.5 cm）。组织学上，4个肿瘤由原始小圆形细胞至上皮样细胞与可变梭形细胞混合组成，而3个肿瘤仅由小圆形细胞至上皮样细胞组成，1个肿瘤主要由高级梭形细胞组成。肿瘤细胞排列成实心片、巢或交叉束。有丝分裂活性范围为 1 至 15/10 HPF（中位数：5/10 HPF）。其他特征包括横纹肌样表型（4/8）、明显的核卷曲（2/8）、显着的基质透明变性（2/8）、局灶性粘液样基质（1/8）、破骨细胞灶（1/8）和坏死（ 1/8）。免疫组织化学显示，所有肿瘤均显示 NUT 蛋白弥漫性强核染色，全细胞角蛋白 (AE1/AE3) (2/8)、CK18 (1/8)、CD99 (3/8)、NKX2.2 (2) 表达不同。 /8)、细胞周期蛋白 D1 (2/8)、结蛋白 (2/8)、BCOR (2/8)、S100 (1/8)、TLE1 (1/8) 和突触素 (1/8)。通过荧光原位杂交分析，8 个肿瘤中有 7 个显示出 NUTM1 重排。 RNA 测序分析分别鉴定了 MXD4::NUTM1 (3/7)、MXI1::NUTM1 (3/7) 和 MGA::NUTM1 (1/7) 融合体。 对 2 例病例进行的基于 DNA 的甲基化分析显示，其甲基化簇与 NUT 癌和未分化的小圆细胞和梭形细胞肉瘤不同。随访时（范围：4至24个月），1名患者在8.5个月时复发，4名患者因转移性疾病存活（诊断后5、10、11和24个月），3名患者状况良好，没有任何转移迹象。复发或转移（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学谱。 NUT 免疫组织化学应纳入单调未分化小圆形、上皮样至难以用常规方法分类的高级别梭形细胞恶性肿瘤的诊断方法中。基于 DNA 的甲基化分析可能为未分化肉瘤的表观遗传学分类提供一种有前景的工具。