Flídrová Miroslava, Hájková Nikola, Hojný Jan, Dvořák Jiří, Michálková Romana, Krkavcová Eva, Laco Jan, McCluggage W Glenn, Giordano Giovanna, Silini Enrico Maria, Michalová Květoslava, Bizoń Magdalena, Němejcová Kristýna, Dundr Pavel, Kendall Bártů Michaela
Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
Mod Pathol. 2024 Dec;37(12):100611. doi: 10.1016/j.modpat.2024.100611. Epub 2024 Sep 10.
Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare tumor of uncertain lineage and low malignant potential. Most tumors behave in a benign manner, but a subset of UTROSCT exhibit an aggressive clinical course with recurrences and metastases. The recurrent molecular alterations in UTROSCT mostly represent gene fusions involving NCOA1-3. We performed a comprehensive clinicopathological, morphologic, immunohistochemical, and molecular analysis on a cohort of 35 UTROSCT. The tumors exhibited various architectural patterns (diffuse, corded/trabecular, tubular, sertoliform, fascicular, whorled, nested, microfollicular, and pseudoglandular), often in combination. The immunohistochemical analysis confirmed the polyphenotypic immunoprofile, often with coexpression of sex cord-stromal, smooth muscle, and epithelial markers, as well as hormone receptors. Next-generation sequencing RNA analysis revealed recurrent NCOA1-3 gene fusions in 22/32 analyzed cases (69%), including ESR1::NCOA3 (11/22), GREB1::NCOA2 (7/22), ESR1::NCOA2 (3/22), and GREB1::NCOA1 (1/22). Tumor mutation burden was low in all cases. The fusion-positive cases exhibited statistically significant association with whorled architecture, conversely necrosis was associated with fusion-negative status. We did not find a significant relationship between any architectural pattern and GREB1 alterations, but the NCOA2-altered tumors were associated with pseudoglandular architecture. The GREB1-altered cases occurred in older patients and tended to be more often intramural masses compared with ESR1-altered cases. On the contrary, the ESR1-altered cases presented more often like submucosal or polypoid tumors. Two tumors exhibited aggressive behavior with recurrent disease. Both of these cases harbored a GREB1::NCOA2 fusion. Unsupervised hierarchical cluster analysis of our cohort revealed 2 main clusters. The tumors with GREB1 or NCOA2 fusion cluster together, suggesting that there are underlying molecular differences between these cases and cases with ESR1::NCOA3 fusion or without fusion. Our findings contribute to the growing knowledge about a rare neoplasm with currently uncertain biological behavior.
子宫肿瘤样卵巢性索肿瘤（UTROSCT）是一种谱系不明、恶性潜能低的罕见肿瘤。大多数肿瘤表现为良性，但一部分UTROSCT呈现侵袭性临床病程，可复发和转移。UTROSCT中反复出现的分子改变大多表现为涉及NCOA1 - 3的基因融合。我们对35例UTROSCT病例进行了全面的临床病理、形态学、免疫组化和分子分析。肿瘤呈现出各种结构模式（弥漫性、条索状/小梁状、管状、睾丸样、束状、漩涡状、巢状、微滤泡状和假腺管状），且常混合存在。免疫组化分析证实了其多表型免疫特征，常同时表达性索间质、平滑肌和上皮标志物以及激素受体。二代测序RNA分析显示，在22/32例分析病例（69%）中存在反复出现的NCOA1 - 3基因融合，包括ESR1::NCOA3（11/22）、GREB1::NCOA2（7/22）、ESR1::NCOA2（3/22）和GREB1::NCOA1（1/22）。所有病例的肿瘤突变负荷均较低。融合阳性病例与漩涡状结构在统计学上具有显著相关性，相反，坏死与融合阴性状态相关。我们未发现任何结构模式与GREB1改变之间存在显著关系，但NCOA2改变的肿瘤与假腺管状结构相关。与ESR1改变的病例相比，GREB1改变的病例发生在老年患者中，且更常为肌壁内肿块。相反，ESR1改变的病例更常表现为黏膜下或息肉样肿瘤。有2例肿瘤表现出侵袭性行为且疾病复发。这两例均存在GREB1::NCOA2融合。对我们队列的无监督层次聚类分析揭示了2个主要聚类。具有GREB1或NCOA2融合的肿瘤聚集在一起，表明这些病例与具有ESR1::NCOA3融合或无融合的病例之间存在潜在的分子差异。我们的研究结果有助于增加对这种目前生物学行为尚不确定的罕见肿瘤的认识。
