Malignant melanotic Xp11 neoplasms exhibit a clinicopathological spectrum and gene expression profiling akin to alveolar soft part sarcoma: a proposal for reclassification.

Wang, Xiao-Tong; Fang, Ru; Zhang, Ru-Song; Ye, Sheng-Bing; Li, Rui; Wang, Xuan; Pan, Rui; Liu, Chong; Chen, Jie-Yu; Zhao, Ming; Teng, Xiao-Dong; Yu, Wen-Juan; Li, Yu-Jun; Wang, Feng-Hua; Zhang, Jian-Guo; Yang, Qi-Chang; Zhang, Yong-Sheng; Lu, Zhen-Feng; Ma, Heng-Hui; Zhou, Xiao-Jun; Xia, Qiu-Yuan; Rao, Qiu

The classification of the distinct group of mesenchymal neoplasms, first described as 'Xp11 translocation perivascular epithelioid cell tumor (PEComa)' and for which recently the term 'melanotic Xp11 neoplasm' or 'Xp11 neoplasm with melanocytic differentiation' has been proposed, remains challenging and controversial. We collected 27 melanotic Xp11 neoplasms, the largest series to date, for a comprehensive evaluation. Fourteen of the cases, along with 8 alveolar soft part sarcomas (ASPS), 9 conventional PEComas, and a control group of 7 normal tissues were submitted to RNA sequencing. Follow-up available in 22 patients showed 5-year overall survival (OS) and 5-year disease-free survival (DFS) of 47.6 and 35.7% respectively, which were similar to ASPS and significantly worse than conventional PEComa. Univariate analysis of location (occurring in the kidney versus not kidney), infiltrative growth pattern, nuclear pleomorphism, mitotic activity ≥2/50 HPF, necrosis, and lymphovascular invasion were found to be associated with OS and/or DFS. Multivariate analysis identified that location was the only factor found to independently correlate with DFS. More importantly, RNA sequencing-based clustering analysis segregated melanotic Xp11 neoplasm and ASPS, clearly from other tumors including conventional PEComa and Xp11 translocation renal cell carcinoma (RCC) and formed a compact cluster representative of the largely similar expression signature. In this study, we first clearly define the true biologic nature that melanotic Xp11 neoplasms are distinctive malignant mesenchymal tumors, rather than simply PEComa variants with occasionally unpredictable behavior. Meanwhile, melanotic Xp11 neoplasm and ASPS more likely represent phenotypic variants of the same entity, which is distinct from conventional PEComa and Xp11 translocation RCC. Based on these important findings, melanotic Xp11 neoplasm might be reclassified into a distinctive entity together with ASPS, independent from PEComa, in the future revisions of the current World Health Organization categories of tumors of soft tissue and bone for the improved reclassification. This article is protected by copyright. All rights reserved.