Warmke Laura M, Ameline Baptiste, Fritchie Karen J, Dehner Carina A, Agaimy Abbas, Din Nasir Ud, Miettinen Markku M, Dermawan Josephine K, Gross John M, Thangaiah Judith J, Chrisinger John S A, Suster David I, Perret Raul, Le Loarer François, Charville Gregory W, Buehler Darya, Yeung Maximus C F, Smith Benjamin F, Baumhoer Daniel, Davis Jessica L
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 350 W. 11thStreet, Room 4086, Indianapolis, IN, 46202, USA.
Bone Tumor Reference Center at the Institute of Pathology, University Hospital Basel and University of Basel, Basel, Switzerland.
Virchows Arch. 2025 Mar;486(3):457-477. doi: 10.1007/s00428-024-03995-2. Epub 2024 Dec 6.
Sclerosing epithelioid fibrosarcoma (SEF) was originally described as a peculiar variant of fibrosarcoma in 1995. Subsequent studies showed that conventional SEF was associated with both immunohistochemical expression of MUC4 and EWSR1/FUS gene rearrangements with CREB3L1 as the predominant fusion partner. Since then, a distinct group of fibrous tumors characterized by YAP1::KMT2A and KMT2A::YAP1 gene rearrangements and SEF-like morphology has been described. These YAP1::KMT2A-rearranged sarcomas were further shown to lack both immunohistochemical expression of MUC4 and canonical EWSR1/FUS gene rearrangements. To better understand whether the YAP1::KMT2A-rearranged sarcomas represent a subset of MUC4-negative SEF or a distinct entity, we studied 22 cases of YAP1::KMT2A-rearranged sarcomas, the largest series to date, and performed a literature review of all previously reported next-generation sequencing (NGS)-confirmed cases. These sarcomas often arose in young adults with a median age of 38 years and a male to female (M:F) ratio of 1.4:1. They predominantly involved somatic soft tissue; however, we report the first case of a tumor that primarily developed inside bone. Immunohistochemical studies showed that the tumors often demonstrated expression of YAP1 and EMA, while all tested cases were negative for MUC4. NGS confirmed the presence of YAP1::KMT2A gene fusions in all cases, some of which initially had false negative results with targeted FISH and solid tumor panel testing. Clinical follow-up information was available in 14 patients with a median follow-up of 25 months (range 1 to 170 months). Local recurrence occurred in three patients (21%) and metastasis developed in seven patients (50%). DNA methylation analysis further showed that YAP1::KMT2A-rearranged sarcomas formed a distinct cluster, which was clearly separate from both conventional SEF and low-grade fibromyxoid sarcoma (LGFMS). These results suggest that YAP1::KMT2A-rearranged sarcomas likely represent a unique sarcoma subtype with propensity for aggressive behavior.
硬化性上皮样纤维肉瘤（SEF）最初于1995年被描述为纤维肉瘤的一种特殊变体。随后的研究表明，传统的SEF与MUC4的免疫组化表达以及EWSR1/FUS基因重排均有关，其中以CREB3L1作为主要融合伴侣。从那时起，已经描述了一组独特的纤维性肿瘤，其特征为YAP1::KMT2A和KMT2A::YAP1基因重排以及SEF样形态。这些YAP1::KMT2A重排的肉瘤进一步显示缺乏MUC4的免疫组化表达和典型的EWSR1/FUS基因重排。为了更好地了解YAP1::KMT2A重排的肉瘤是代表MUC4阴性SEF的一个子集还是一个独特的实体，我们研究了22例YAP1::KMT2A重排的肉瘤，这是迄今为止最大的一组病例，并对所有先前报道的经下一代测序（NGS）确认的病例进行了文献综述。这些肉瘤常发生于年轻人，中位年龄为38岁，男女比例为1.4:1。它们主要累及躯体软组织；然而，我们报告了首例主要发生于骨内的肿瘤。免疫组化研究表明，这些肿瘤常显示YAP1和EMA表达，而所有检测病例的MUC4均为阴性。NGS证实所有病例均存在YAP1::KMT2A基因融合，其中一些病例最初在靶向FISH和实体瘤检测板检测中出现假阴性结果。14例患者有临床随访信息，中位随访时间为25个月（范围1至170个月）。3例患者（21%）发生局部复发，7例患者（50%）发生转移。DNA甲基化分析进一步表明，YAP1::KMT2A重排的肉瘤形成一个独特的聚类，明显不同于传统的SEF和低级别纤维黏液样肉瘤（LGFMS）。这些结果表明，YAP1::KMT2A重排的肉瘤可能代表一种具有侵袭性行为倾向的独特肉瘤亚型。
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