Abstract：
Malignant gastrointestinal neuroectodermal tumors (MGNETs), also known as \"gastrointestinal clear cell sarcoma-like tumors\", are very rare, aggressive sarcomas characterized by enteric location, distinctive pathologic features, and EWSR1/FUS::ATF1/CREB1 fusions. Despite identical genetics, the clinicopathologic features of MGNET are otherwise quite different from those of clear cell sarcoma of soft parts. Only exceptional extraenteric MGNET (E-MGNET) has been reported. We report a series of 11 E-MGNETs, the largest to date. Cases diagnosed with MGNET and occurring in nonintestinal locations were retrieved. A clinical follow-up was obtained. The tumors occurred in 3 men and 8 women (range, 14-70 years of age; median, 33 years) and involved the soft tissues of the neck (3), shoulder (1), buttock (2), orbit (1), tongue/parapharyngeal space (1), urinary bladder (1), and falciform ligament/liver (1). Tumors showed morphologic features of enteric MGNET (small, relatively uniform, round to ovoid cells with round, regular nuclei containing small nucleoli growing in multinodular and vaguely lobular patterns, with solid, pseudoalveolar, and pseudopapillary architecture). Immunohistochemical results were S100 protein (11/11), SOX10 (11/11), synaptophysin (3/10), CD56 (7/9), CD117 (3/9), DOG1 (0/4), ALK (4/8), chromogranin A (0/10), HMB-45 (0/11), Melan-A (0/11), tyrosinase (0/4), and MiTF (0/11). Next-generation sequencing results were EWSR1::ATF1 (7 cases), EWSR1::CREB1 (3 cases), and EWSR1::PBX1 (1 case). The EWSR1::PBX1-positive tumor was similar to other cases, including osteoclast-like giant cells, and negative for myoepithelial markers. A clinical follow-up (range, 10-70 months; median, 34 months) showed 4 patients dead of disease (10.5, 12, 25, and 64 months after diagnosis), 1 patient alive with extensive metastases (43 months after diagnosis), 1 patient alive with persistent local disease (11 months after diagnosis), and 4 alive without disease (10, 47, 53, and 70 months after diagnosis). One case is too recent for the follow-up. The clinicopathologic and molecular genetic features of rare E-MGNET are essentially identical to those occurring in intestinal locations. Otherwise, typical E-MGNET may harbor EWSR1::PBX1, a finding previously unreported in this tumor type. As in enteric locations, the behavior of E-MGNET is aggressive, with metastases and/or death from disease in at least 50% of patients. E-MGNET should be distinguished from clear cell sarcoma of soft parts and other tumors with similar fusions. ALK expression appears to be a common feature of tumors harboring EWSR1/FUS::ATF1/CREB1 fusion but is unlikely to predict the therapeutic response to ALK inhibition. Future advances in our understanding of these unusual tumors will hopefully lead to improved nomenclature.
摘要：
恶性胃肠道神经外胚层肿瘤（MGNET），又称“胃肠道透明细胞肉瘤样肿瘤”，非常罕见，侵袭性肉瘤以肠定位为特征，独特的病理特征，和EWSR1/FUS::ATF1/CREB1融合。尽管基因相同,MGNET的临床病理特征与软组织透明细胞肉瘤（CCS）完全不同。仅报道了异常肠外MGNET(E-MGNET)。我们报道了一系列11个E-MGNET，迄今为止最大的。检索诊断为MGNET并发生在非肠道位置的病例。获得临床随访。肿瘤发生在3名男性和8名女性（14-70岁，中位数33年），并累及颈部软组织（3），肩部(1),臀部（2），轨道(1),和舌/咽旁间隙（1），膀胱（1）和镰状韧带/肝脏（1）。肿瘤显示肠MGNET的形态学特征(小，相对均匀,圆形到卵圆形细胞，含有小核仁的规则核，以多结节和模糊的小叶图案生长，与固体，假肺泡和假乳头结构）。免疫组织化学结果为：S100蛋白（11/11），SOX10(11/11),突触素（3/10），CD56(7/9),CD117(3/9),DOG1(0/4),ALK(4/8),嗜铬粒蛋白A（0/10），HMB45(0/11),Melan-A(0/11),酪氨酸酶（0/4），MiTF(0/11)。NGS结果为：EWSR1::ATF1（7例），EWSR1::CREB1(3例)和EWSR1::PBX1(1例)。EWSR1::PBX1阳性肿瘤与其他病例相似，包括破骨细胞样巨细胞,肌上皮标志物阴性.临床随访（范围：10至70个月；中位数34个月）显示4例患者死于疾病（诊断后10.5、12、25和64个月），1例有广泛转移的患者（诊断后43个月），1例患者持续局部疾病（诊断后11个月），和4个活着没有疾病（诊断后10、47、53和70个月）。一个案例太近，无法跟进。罕见的E-MGNET的临床病理和分子遗传学特征与肠道部位的特征基本相同。其他典型的E-MGNET可能含有EWSR1::PBX1，这是以前在这种肿瘤类型中未报道的发现。与在肠道位置一样，E-MGNET的行为具有攻击性，至少50％的患者发生疾病转移和/或死亡。E-MGNET应与CCS和其他具有相似融合的肿瘤区分开。ALK表达似乎是具有EWSR1/FUS::ATF1/CREB1融合的肿瘤的共同特征，但不太可能预测对ALK抑制的治疗反应。我们对这些不寻常肿瘤的理解的未来进展将有望导致改进的命名法。
