Abstract：
Deficiency of fumarate hydratase (FH) protein expression in uterine corpus leiomyomas may be attributable to either germline or somatic mutations of the FH gene, the former being definitional for the hereditary leiomyomatosis and renal cell cancer syndrome. The authors assess whether, using previously reported FH-associated morphologic features, FH protein-deficient uterine corpus leiomyomas associated with a pathogenic germline mutations of the FH gene (group 1) are distinguishable from FH protein-deficient uterine corpus leiomyomas without such mutations (and whose FH protein loss is presumed to be attributable to somatic/epigenetic inactivation or other unknown phenomena: group 2). Groups 1 and 2 were compared regarding a variety of clinicopathologic features, including 7 core \"FH-associated\" tumoral morphologic features: staghorn vasculature; alveolar-type edema; bizarre nuclei; chain-like tumor nuclei; hyaline cytoplasmic globules; prominent nucleoli, intranuclear inclusions, and perinucleolar halos; and prominent eosinophilic/fibrillary cytoplasm. Among 2418 patients diagnosed with uterine corpus leiomyoma during the study period, FH-associated morphologic features were reported in 1.5% (37 patients), and FH immunohistochemistry was performed in 29 (1.19%). Fourteen (48.27%) of the 29 patients showed FH protein deficiency by immunohistochemistry. Twelve patients underwent germline testing, of which 8 (66.7%) were classified as group 1 and 4 (33.3%) as group 2. FH protein-deficient tumors were larger (10.44 vs 4.08 cm, P = 0.01) and associated with younger patients (42.05 vs 47.97, P = 0.004) than 370 randomly selected uterine leiomyoma controls. Groups 1 and 2 showed no significant differences in patient age and tumor size. In group 1 tumors, the FH-associated morphologic features were generally present diffusely; all group 1 tumors displayed ≥5 FH-associated features, whereas all group 2 tumors displayed <5 FH-associated features (means 6.5 ± 0.53 vs 3.5 ± 1.00, P < 0.001). Notably, eosinophilic/fibrillary cytoplasm and alveolar-type edema were each significantly more prevalent in group 1 tumors than group 2 tumors (P = 0.018 for both). No single morphologic feature was found to be completely sensitive and specific in making the distinction between group 1 and 2 tumors. Our findings suggest that groups 1 and 2 are unlikely to be morphologically distinguishable by individual morphologic features. Whether there is a combination of features that can reliably make this distinction is unclear and will require additional studies with larger cohorts.
摘要：
子宫平滑肌瘤中富马酸水合酶（FH）蛋白表达的缺乏可能归因于FH基因的种系或体细胞突变，前者定义为遗传性平滑肌瘤病和肾细胞癌综合征。作者评估是否，使用先前报道的FH相关形态学特征，与FH基因的致病性种系突变相关的FH蛋白缺陷型子宫平滑肌瘤(第1组)可与没有这种突变的FH蛋白缺陷型子宫平滑肌瘤(并且其FH蛋白丢失被认为可归因于体细胞/表观遗传失活或其他未知现象:第2组)区分开。比较了第1组和第2组的各种临床病理特征，包括7个核心“FH相关”肿瘤形态学特征：鹿角状血管；肺泡型水肿；奇异核；链样肿瘤核；透明细胞质球；突出的核仁，核内包裹体,和核仁周围晕；和突出的嗜酸性/原纤维细胞质。在研究期间诊断为子宫平滑肌瘤的2418例患者中，据报道，FH相关的形态学特征为1.5％（37例），29例(1.19%)进行FH免疫组化。29例患者中有14例（48.27％）通过免疫组织化学显示FH蛋白缺乏。12名患者接受了种系测试，其中8人(66.7%)归为第1组,第4人(33.3%)归为第2组.FH蛋白缺陷的肿瘤更大（10.44vs4.08cm，P=0.01），与370名随机选择的子宫平滑肌瘤对照组相比，年轻患者（42.05vs47.97，P=0.004）相关。第1组和第2组在患者年龄和肿瘤大小方面没有显着差异。在第1组肿瘤中，FH相关的形态学特征通常呈弥漫性；所有第1组肿瘤均显示≥5个FH相关特征，而所有第2组肿瘤均显示<5个FH相关特征（平均6.5±0.53vs3.5±1.00，P<0.001）。值得注意的是,第1组肿瘤中嗜酸性粒细胞/原纤维细胞质和肺泡型水肿均明显高于第2组肿瘤(两者P=0.018)。在区分第1组和第2组肿瘤时，没有发现单一的形态学特征是完全敏感和特异的。我们的发现表明，第1组和第2组不太可能通过单个形态特征在形态上可区分。是否存在能够可靠地进行这种区分的特征组合尚不清楚，并且需要进行更大的队列研究。
