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Fumarate Hydratase-deficient Uterine Leiomyomas Occur in Both the Syndromic and Sporadic Settings.

综合征和散发性病例中的延胡索酸水合酶缺陷性子宫平滑肌瘤

Harrison WJ,Andrici J,Maclean F,Madadi-Ghahan R,Farzin M,Sioson L,Toon CW,Clarkson A,Watson N,Pickett J,Field M,Crook A,Tucker K,Goodwin A,Anderson L,Srinivasan B,Grossmann P,Martinek P,Ondič O,Hes O,Trpkov K,Clifton-Bligh RJ,Dwight T,Gill AJ

Abstract

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome secondary to germline fumarate hydratase (FH) mutation presents with cutaneous and uterine leiomyomas, and a distinctive aggressive renal carcinoma. Identification of HLRCC patients presenting first with uterine leiomyomas may allow early intervention for renal carcinoma. We reviewed the morphology and immunohistochemical (IHC) findings in patients with uterine leiomyomas and confirmed or presumed HLRCC. IHC was also performed on a tissue microarray of unselected uterine leiomyomas and leiomyosarcomas. FH-deficient leiomyomas underwent Sanger and massively parallel sequencing on formalin-fixed paraffin-embedded tissue. All 5 patients with HLRCC had at least 1 FH-deficient leiomyoma: defined as completely negative FH staining with positive internal controls. One percent (12/1152) of unselected uterine leiomyomas but 0 of 88 leiomyosarcomas were FH deficient. FH-deficient leiomyoma patients were younger (42.7 vs. 48.8 y, P=0.024) and commonly demonstrated a distinctive hemangiopericytomatous vasculature. Other features reported to be associated with FH-deficient leiomyomas (hypercellularity, nuclear atypia, inclusion-like nucleoli, stromal edema) were inconstantly present. Somatic FH mutations were identified in 6 of 10 informative unselected FH-deficient leiomyomas. None of these mutations were found in the germline. We conclude that, while the great majority of patients with HLRCC will have FH-deficient leiomyomas, 1% of all uterine leiomyomas are FH deficient usually due to somatic inactivation. Although IHC screening for FH may have a role in confirming patients at high risk for hereditary disease before genetic testing, prospective identification of FH-deficient leiomyomas is of limited clinical benefit in screening unselected patients because of the relatively high incidence of somatic mutations.

摘要

继发于延胡索酸水合酶(FH)胚系突变的遗传性平滑肌瘤病和肾细胞癌(HLRCC)综合征表现为皮肤和子宫平滑肌瘤及显著侵袭性肾细胞癌。识别首发症状为子宫平滑肌瘤的HLRCC患者可早期干预肾癌。

我们复习了子宫平滑肌瘤患者肿瘤的形态学和免疫组化(IHC)所见,并证实或推测为HLRCC。未经选择的子宫平滑肌瘤和平滑肌肉瘤组织微阵列也行IHC检测。福尔马林固定石蜡包埋的FH缺陷平滑肌瘤组织行Sanger和大规模平行测序。

所有5名HLRCC患者至少有1个FH缺陷平滑肌瘤:定义为FH染色完全阴性,内对照阳性。百分之一(12/1152)未经选择的子宫平滑肌瘤FH缺陷,88例子宫平滑肌肉瘤未见FH缺陷。FH缺陷平滑肌瘤患者较年轻(42.7vs.48.8y,p=0.024),普遍呈显著血管外皮瘤样脉管。其他已报道的与FH缺陷平滑肌瘤相关的特征(高度富于细胞,核非典型性,包涵体样核仁,间质水肿)随机出现。10例信息详尽未经选择的FH缺陷平滑肌瘤中,6例为体系FH突变。胚系未发现这些突变。

我们推断,虽然大多数HLRCC患者会发生FH缺陷平滑肌瘤,但全部子宫平滑肌瘤中仍有1%FH缺陷病例通常由体系失活引起。尽管遗传学检测之前IHC筛查FH对确定患者处于遗传性疾病高发风险具有作用,但筛查未经选择的患者以预期识别FH缺陷平滑肌瘤临床意义有限,因为有相当高的体细胞性突变发生率。

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