Int J Gynecol Pathol. 2023 Mar 1;42(2):120-135. doi: 10.1097/PGP.0000000000000918. Epub 2022 Dec 5.
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%的子宫平滑肌瘤存在富马酸水合酶（FH）缺陷（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尚不清楚。收集了 348 例 uLMS 的临床病理数据。记录了与 FH 缺乏相关的形态特征（鹿角型血管、肺泡样水肿、核周晕状空泡、嗜酸性细胞质包涵体和链状核排列）。所有 348 例肿瘤均通过 FH 免疫组化进行研究。89 例还通过 S-（2-琥珀酰）半胱氨酸（2SC）免疫组化进行研究。鉴定出 7 例（2%）FHd uLMS。5 例 FH 呈均匀阴性，2SC 弥漫阳性染色；1 例 FH 表现为不均一的阴性至弱阳性，2SC 弥漫阳性染色；1 例 FH 保留，2SC 阳性局限于形态上不同的亚克隆。7 例患者中有 3 例在就诊时存在子宫外疾病，6 例中有 3 例疾病持续存在或死于疾病。核周晕状空泡的大核仁在 FHd uLMS 中（7/7）明显比在 FH 保留的 uLMS 中更常见（182/341；P=0.017）。FHd 和 FH 保留肿瘤之间的疾病特异性生存率、无病生存率和 FH 缺乏的其他形态特征没有显著差异。我们的数据强调，免疫组化 FH 缺乏并不能排除子宫平滑肌肿瘤的恶性。然而，uLMS 中 FH 缺乏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，需要更大的多机构努力来收集足够的 FHd uLMS，以便更有力地进行临床病理和分子特征分析。
