Approximately 1% to 1.5% of uterine leiomyomas are fumarate hydratase (FH)-deficient (FHd). A subset of these are associated with germline FH mutations. However, the prevalence and clinicopathologic characteristics of FHd uterine leiomyosarcoma (uLMS) remain unknown. Clinicopathologic data were collected for 348 uLMS. Morphologic features associated with FH deficiency (staghorn-type vessels, alveolar-pattern edema, macronucleoli with perinucleolar clearing, eosinophilic cytoplasmic inclusions, and chain-like nuclear arrangement) were documented. All 348 tumors were studied by FH immunohistochemistry. Eighty-nine were also studied by S-(2-succinyl)-cysteine (2SC) immunohistochemistry. Seven (2%) FHd uLMS were identified. Five showed uniformly negative FH and diffusely positive 2SC immunostaining; 1 showed variably negative to weak to strong FH and diffusely positive 2SC immunostaining; and 1 showed retained FH staining alongside positive 2SC confined to a morphologically distinct subclone. Three of 7 patients had extrauterine disease at presentation, and 3 of 6 had persistent disease or died from disease. Macronucleoli with perinucleolar clearing were significantly more common in FHd uLMS (7/7) than in uLMS with retained FH (182/341; P=0.017). Disease-specific survival, disease-free survival, and other morphologic features of FH deficiency did not differ significantly between FHd and FH-retained tumors. Our data emphasize that immunohistochemical FH deficiency does not preclude malignancy in uterine smooth muscle tumors. However, the biological significance and molecular basis of FH deficiency in uLMS, including any relationship to germline FH mutation, remain unknown, and a larger multi-institutional effort is necessary to gather sufficient FHd uLMS for more robustly powered clinicopathologic and for molecular characterization.

大约 1% 至 1.5% 的子宫肌瘤缺乏富马酸水合酶 (FH) (FHd)。其中一部分与种系 FH 突变有关。然而，FHd 子宫平滑肌肉瘤 (uLMS) 的患病率和临床病理特征仍然未知。收集了 348 uLMS 的临床病理数据。记录了与 FH 缺陷相关的形态特征（鹿角型血管、肺泡型水肿、核仁周围透明的大核仁、嗜酸性细胞质包涵体和链状核排列）。所有 348 个肿瘤均通过 FH 免疫组织化学进行了研究。还通过 S-(2-琥珀酰)-半胱氨酸 (2SC) 免疫组织化学研究了 89 例。确定了七个 (2%) FHD uLMS。其中 5 例显示 FH 免疫染色一致呈阴性，2SC 免疫染色呈弥漫性阳性；[0070] 1显示不同程度的阴性到弱到强的FH和弥漫性阳性的2SC免疫染色；1 显示保留的 FH 染色与阳性 2SC 一起局限于形态上不同的亚克隆。7 名患者中的 3 名就诊时患有宫外疾病，6 名患者中的 3 名患有持续性疾病或死于疾病。FHd uLMS (7/7) 中具有核仁周围清除的大核明显比保留 FH 的 uLMS 中更常见 (182/341；P = 0.017)。FH 缺陷的疾病特异性生存率、无病生存率和其他形态学特征在 FHd 和 FH 保留肿瘤之间没有显着差异。我们的数据强调，免疫组织化学 FH 缺陷并不能排除子宫平滑肌肿瘤的恶性肿瘤。然而，uLMS 中 FH 缺陷的生物学意义和分子基础，包括与种系FH突变的任何关系，仍然未知，并且需要更大的多机构努力来收集足够的 FHd uLMS，以进行更强大的临床病理学和分子表征。