Zhang Qing, Poropatich Kate, Ubago Julianne, Xie Jia, Xu Xiuhua, Frizzell Norma, Kim Julie, Kong Beihua, Wei Jian-Jun
Departments of Pathology (Q.Z., K.P., J.U., J.X., X.X., J.-J.W.) Gynecology and Obstetrics (J.K., J.-J.W.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China (Q.Z., B.K.) Department of Pharmacology, Physiology & Neuroscience, University of South Carolina, Columbia, South Carolina (N.F.).
Int J Gynecol Pathol. 2018 Sep;37(5):421-430. doi: 10.1097/PGP.0000000000000447.
Leiomyoma with bizarre nuclei (LM-BN), is a variant of uterine smooth muscle tumor with atypical histologic features. Although some LM-BN share several significant genetic alterations with leiomyosarcoma, including p16 and p53, the underlying tumorigenesis of LM-BN remains largely unknown. As we previously reported, LM-BN can be divided into 2 subtypes, type I and type II, based on different nuclear features. Type I LM-BN have similar histologic features as uterine smooth muscle tumors with fumarate hydratase (FH) alterations. In this study, we examined FH expression and FH mutations in 77 LM-BN (40 type I cases and 37 type II cases). FH expression was examined by immunohistochemistry using S-(2-succino)-cysteine antibodies (2SC, a protein modification associated with FH inactivation and subsequent fumarate accumulation) and FH antibodies (FH gene products). Seventy-two LM-BN tumors underwent Sanger sequencing to detect FH mutations. We found that 51% (39/77) of LM-BN showed FH alterations detected by immunohistochemistry with both 2SC and FH. Mutational analysis showed that 21% (15/72) of LM-BN harbored FH gene mutations. Further analysis revealed that 85% (34/40) of those with FH alterations were type I LM-BN while 19% (7/37) were type II LM-BN. Our findings suggest that over half of histologically diagnosed LM-BN may be related to FH alterations or FH mutations and the majority of these have the characteristic histologic features of type I LM-BN.
伴有奇异核的平滑肌瘤（LM-BN）是一种具有非典型组织学特征的子宫平滑肌肿瘤变体。尽管一些LM-BN与平滑肌肉瘤有若干显著的基因改变，包括p16和p53，但LM-BN的潜在肿瘤发生机制在很大程度上仍不清楚。正如我们之前所报道的，LM-BN可根据不同的核特征分为I型和II型两种亚型。I型LM-BN具有与伴有富马酸水合酶（FH）改变的子宫平滑肌肿瘤相似的组织学特征。在本研究中，我们检测了77例LM-BN（40例I型和37例II型）中的FH表达和FH突变。使用S-（2-琥珀酰）-半胱氨酸抗体（2SC，一种与FH失活及随后的富马酸积累相关的蛋白质修饰）和FH抗体（FH基因产物）通过免疫组织化学检测FH表达。72例LM-BN肿瘤进行了桑格测序以检测FH突变。我们发现，51%（39/77）的LM-BN通过2SC和FH免疫组织化学检测显示有FH改变。突变分析表明，21%（15/72）的LM-BN存在FH基因突变。进一步分析显示，有FH改变的病例中85%（34/40）为I型LM-BN，而19%（7/37）为II型LM-BN。我们的研究结果表明，超过一半经组织学诊断的LM-BN可能与FH改变或FH突变有关，并且其中大多数具有I型LM-BN的特征性组织学特征。
