血管生成相关分子在静脉内平滑肌瘤中的表达特征及其诊断价值

Expression characteristics and diagnostic value of angiogenic molecules in intravenous leiomyomatosis

目的分析静脉内平滑肌瘤(IVL)患者的临床病理特征,探讨血管生成相关分子在IVL中的表达特点及诊断价值。方法回顾性分析浙江大学医学院附属妇产科医院2013年1月至2021年4月收治的40例IVL患者的临床病理资料,Log-rank检验比较不同特征患者的无复发生存(RFS)率的差异。对10个血管生成相关分子进行免疫组织化学(IHC)染色,分析其在IVL中的表达特点,计算表达率高的分子诊断IVL的灵敏度和特异度,绘制受试者工作特征(ROC)曲线,并计算ROC曲线下面积(AUC),评估诊断价值。结果 40例IVL患者年龄[M(Q1,Q3)]为47(43,50)岁,临床表现不典型,术前超声诊断准确率为12.5%(5/40),CT和(或)磁共振成像(MRI)诊断准确率为26.7%(8/30),术中冰冻切片诊断准确率为30.0%(12/40)。IVL总体复发率为10.0%(4/40)。Log-rank检验结果显示,既往有剖宫产史的IVL患者的累积RFS率(40.9%)低于无剖宫产史者(96.4%)(P<0.05);中位RFS时间短于无剖宫产史者(16.4比22.2个月)。肾上腺髓质素(ADM)、成纤维细胞生长因子受体1(FGFR1)、血管内皮生长因子受体3(VEGFR3)和血管生成素受体酪氨酸激酶受体1(TIE1)在IVL中的总体阳性率分别为65.0%(26/40)、75.0%(30/40)、57.5%(23/40)和50.0%(20/40)。肿瘤最大径>5 cm者FGFR1表达强度和阳性率高于肿瘤最大径<5 cm者(P<0.05)。绘制ROC曲线发现,FGFR1联合ADM、VEGFR3和TIE1诊断IVL的AUC为0.876(95%CI:0.788~0.964,P<0.001)。结论 IVL临床表现无特异性,既往有剖宫产史者累积RFS率低,复发间隔较短,影像学及冰冻切片诊断率低。FGFR1与ADM、VEGFR3、TIE1在IVL中均呈高表达,四者联合应用诊断IVL的效能高于影像学及经典的血管内皮标志物的诊断水平。

Objective This study aims to analyze the clinicopathological characteristics of patients with intravenous leiomyoma(IVL),and to explore the expression characteristics and diagnostic value of angiogenesis related molecules in IVL.Methods The clinicopathological data of 40 patients with IVL at Women′s Hospital,School of Medicine,Zhejiang University from January 2013 to April 2021 were reviewed.Log-rank test was performed to compare the difference in recurrence-free survival(RFS)rates among patients with different clinicopathological characteristics.Immunohistochemistry(IHC)staining was performed on 10 angiogenesis related molecules to analyze their expression characteristics in IVL.The sensitivity and specificity of molecules with high expression rates in the diagnosis of IVL were calculated,the receiver operating characteristic curve(ROC)was plotted and the area under ROC(AUC)was calculated to evaluate the diagnostic value.Results Median age of the 40 patients was 47(43,50)years.The clinical manifestations of IVL were atypical with the diagnostic accuracy of preoperative ultrasound was 12.5%(5/40),CT and/or MRI was 26.7%(8/30),and intraoperative frozen section was 30.0%(12/40).The overall recurrence rate of IVL was 10.0%(4/40).The Log-rank test showed that the cumulative recurrence-free survival rate of IVL patients with previous cesarean section(40.9%)was lower than that of those without cesarean section(96.4%)(P<0.05);and their median RFS time was shorter than those without cesarean section(16.4 months vs 22.2 months).The overall positive rates of adrenomedullin(ADM),fibroblast growth factor receptor 1(FGFR1),vascular endothelial growth factor receptor 3(VEGFR3)and angiogenin receptor tyrosine kinase receptor 1(TIE1)were 65.0%(26/40),75.0%(30/40),57.5%(23/40)and 50.0%(20/40),respectively.FGFR1 expression intensity and positive rate were higher in tumors with a maximum diameter greater than 5 cm than in tumors with a maximum diameter smaller than 5 cm(P<0.05).The AUC of FGFR1 combined with ADM,VEGFR3,and TIE1 was 0.876(95%CI:0.788-0.964,P<0.001).Conclusions There was no typical clinical manifestation of IVL.A history of the previous cesarean section indicated a lower cumulative recurrence-free survival rate and shorter recurrence interval.It was hard to diagnose IVL by sonography,radiography,or frozen section pathology.FGFR1,ADM,VEGFR3,and TIE1 were all highly expressed in IVL,and the efficacy of the combination of the four molecules in diagnosing IVL was higher than that of imaging and classical vascular endothelial markers,which are expected to be promising molecular diagnostic markers.