Advances on FBP1’
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摘要: FBP1作为糖异生过程的关键酶，控制糖异生的速率，催化1-6二磷酸果糖不可逆的水解成6-磷酸果糖和无机磷酸盐，从而能够控制糖异生速率，影响细胞糖酵解。近年来，其在癌症中的作用越来越受到重视。研究发现FBP1在多种肿瘤中表达异常，与肿瘤发生、发展及预后关系密切，这些结果对于肿瘤分子标记物、靶向药物研究、预后相关研究表现出良好的前景。Abstract: As a key enzyme in the process of gluconeogenesis, FBP1 controls the rate of gluconeogenesis and catalyzes the irreversible hydrolysis of fructose 1-6 diphosphate into fructose 6-phosphate and inorganic phosphate, thereby controlling the rate of gluconeogenesis and affecting cellular glycolysis. In recent years, its role in malignant tumors has attracted more and more attention. Studies have found that FBP1 is abnormally expressed in a variety of tumors and is closely related to tumor occurrence and prognosis. These results show a good prospect for tumor molecular markers, targeted drug research, and prognosis-related research.
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Key words:
- FBP1 /
- Aerobic glycolysis /
- Warburg effect /
- Cancer
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子宫肌瘤是女性生殖器最常见的良性肿瘤，由平滑肌及结缔组织组成。常见于30～50岁妇女。据尸检统计，30岁以上妇女发病率约20%[1]。按肌瘤与子宫肌壁的关系分为肌壁间肌瘤，黏膜下肌瘤，浆膜下肌瘤。临床症状主要有下腹部包块，经量增多及经期延长，压迫症状，有恶变倾向，严重影响妇女的身心健康[2]。子宫腺肌症为子宫内膜及间质组织异位至子宫肌层，主要分型有弥漫性及局限性。其中子宫腺肌瘤属于局限性子宫腺肌症，是子宫腺肌症的一种特殊类型，在常规超声上与子宫肌瘤有相似表现。临床处理上子宫肌瘤因为有假包膜，可以行瘤体剥除术，而子宫腺肌瘤与子宫肌层无明显界限，手术不能剥除[3]。术前明确诊断子宫肌瘤与子宫腺肌症具有重要的临床意义。静脉超声造影在常规超声基础上通过注射超声造影剂，来增强人体的血流散射信号，实时动态地观察组织的微血管灌注信息，能很大程度提高病变检出率及精准率。该研究通过对子宫肌瘤及子宫腺肌症患者行静脉超声造影检查，分析造影模式及特点，对两者进行鉴别诊断。
1. 资料与方法
1.1 一般资料
选取2017年12月至2019年12月昆明医科大学第一附属医院妇科收治的子宫肌瘤和子宫腺肌症患者共133例，其中子宫腺肌症患者66例，子宫肌瘤患者67例，年龄45～60岁，平均（52.5±3.6）岁；病灶部位的大小3.2～6.5 cm，平均（4.71±1.28）cm。
1.2 仪器与方法
（1）配有造影分析软件的Philips IU Elite彩色多普勒超声诊断仪，阴道探头C10-3v，频率4-8 MHz；腹部探头C5-1，频率3～5 MHz，造影过程采用低机械指数，所有患者检查时仪器参数保持一致。造影剂为意大利Bracco公司生产的Sonovue。使用时先用5 mL注射用生理盐水稀释用力晃荡均匀至悬浮液状态，抽取4.8 mL经肘正中静脉快速团注；（2）首先通过常规超声了解病灶的部位、大小、数目、形状、包膜，内部回声，血液供应情况等，做出初步诊断。将仪器调至造影模式获得最佳切面，以正常子宫肌层作为参照。患者经肘正中静脉快速注入造影剂的同时，超声操作人员启动仪器计时器，固定超声探头实时观察目标区域至少3 min并存储动态图像。必要时进行二次造影，两次造影间隔大于15 min。手动勾画出感兴趣区（region of interest，ROI），运用时间强度曲线（time-intensity curve，TIC）进行定量分析，以相同面积正常子宫肌层作为参照观察病灶区TIC形态，对记录的各项参数做后续分析。各对照参数包括：上升时间（rise time，RT）；达峰时间（time to peak，TP）；峰值强度（peak intensity，PI）。术后病理结果为金标准。
1.3 统计学处理
选用SPSS21.0软件进行统计分析，分类资料用数字和百分比表示，计量资料以均数±标准差表示，计量资料比较采用独立样本t检验，P < 0.05为差异有统计学意义。
2. 结果
2.1 常规超声与静脉超声造影诊断准确率
常规超声、静脉超声造影诊断子宫肌瘤的准确率分别为92%、98%，二者差异有统计学意义（P < 0.05），诊断子宫腺肌症的准确率分别为91%、100%，见表1。
表 1 诊断结果（%）Table 1. Diagnostic results（%）诊断方法 子宫肌瘤 子宫腺肌症 常规阴道超声检查 59/67（92） 60/66（91） 静脉超声造影 66/67（98） 66/66（100） χ2 12.0 23.0 P 0.001 0.011 2.2 超声造影超声影像学表现
子宫肌瘤在超声造影下首先表现为假包膜环状高增强，随后肌瘤内部造影剂呈放射状充填，内部呈均匀等增强或低增强，部分呈不均匀增强，增强晚期早于肌层消退，在造影剂消退时与周边有明显边界，见图1。浆膜下子宫肌瘤造影剂可显示其蒂部血供源于子宫动脉，见图2。
图 1 超声造影显示包块早于子宫肌壁灌注，周边呈典型的环状增强，造影剂呈放射状向包块内部填充Figure 1. Contrast-enhanced ultrasound showed that the mass appeared earlier than the myometrium wall perfusion，with a typical annular enhancement around the periphery，and contrast agent radially filling the mass
图 2 超声造影显示带蒂浆膜下子宫肌瘤，血供来自于子宫动脉Figure 2. Contrast-enhanced ultrasound showed a subserosal uterine fibroid with blood supply from the uterine artery子宫腺肌症典型超声造影表现：与正常的子宫肌层比较，造影剂注入后，首先瘤体血管有造影剂进入并出现短线状增强，达峰后整个瘤体呈现不均匀性低或等增强，造影剂消退时瘤体内部呈低增强，与周边肌层分界不清，造影增强过程中无周边环状增强，与周边没有明显边界，见图3。部分子宫腺肌症可表现为内部无造影剂填充，见图4。
图 3 超声造影显示典型子宫腺肌症包块与子宫肌壁呈同进同退等增强，无周边环状增强Figure 3. Contrast-enhanced ultrasound showed that the typical adenomyosis mass and the uterine muscle wall were enhanced synchronically，without circumferential enhancement
图 4 超声造影显示子宫腺肌症患者，内部无造影剂灌注，为异位子宫内膜在肌壁间周期性出血液化坏死区域Figure 4. Contrast-enhanced ultrasonography showed that in adenomyosis，there was no contrast perfusion inside，and the ectopic endometrium was in the area of periodic bleeding and liquefactive necrosis between muscle walls2.3 超声造影参数对比
超声造影检查中，子宫腺肌症患者始增时间早于子宫肌瘤患者，达峰时间早于子宫肌瘤症患者，峰值强度低于子宫肌瘤患者，差异有统计学意义（P < 0.05），见表2。
表 2 子宫肌瘤与子宫腺肌症超声造影参数对比（$\bar x \pm s$ ）Table 2. Comparison of CEUS parameters between uterine fibroids and adenomyosis（$\bar x \pm s$ ）TIC参数 子宫肌瘤组（n = 67） 子宫腺肌病（n = 66） P 开始时间（s） 17.39 ± 2.45 14.05 ± 2.98 0.000 达峰时间（s） 27.35 ± 3.78 23.59 ± 4.36 0.000 峰值强度（db） 36.23 ± 4.97 28.66 ± 4.67 0.000 子宫腺肌症患者始增时间早于子宫肌瘤患者，达峰时间早于子宫肌瘤症患者，峰值强度低于子宫肌瘤患者。
3. 讨论
子宫肌瘤和子宫腺肌症常见于青中年妇女，两者症状和体征有一定的相似性，合并发病率21%～44%[4]，两者的鉴别诊断主要依靠超声检查。在超声检查过程中，部分子宫肌瘤的假包膜不清楚或子宫腺肌瘤因供血不足与周围分界清楚时，会造成两者的超声鉴别诊断困难[5]。MRI对于子宫肌瘤与子宫腺肌症的鉴别诊断具有较高价值，但MRI检查费用较高，耗时长，对于有幽闭恐惧症患者，有金属节育环置入患者不适用，仅在依靠其它诊断方法不能诊断时才使用[6]。静脉超声造影在常规超声基础上通过注射超声造影剂，来增强人体的血流散射信号，实时动态地观察组织的微血管灌注信息该研究采用的造影剂为第二代造影剂，不溶于水或血液，通过气体排出，超声造影可以增强病灶谐波信号，显示脏器血供及微小病灶。该研究通过静脉超声造影检查观察子宫肌瘤与子宫腺肌症血流灌注模式及特点，能够提高两者的鉴别诊断准确率，为临床提供精准诊断。本研究发现子宫肌瘤与子宫腺肌症呈现出明显不同血流灌注灌注模式，具有特征性改变，可以做为两者的鉴别要点。
子宫肌瘤的假包膜的形成是由肌瘤压迫周围肌壁纤维而形成，子宫动脉主要分支在假包膜处移型为较粗大的血管网包绕瘤体[7]。子宫腺肌症是正常子宫内膜腺体及间质组织侵入到子宫肌层内形成，其病变范围大多局限于子宫肌层内，病灶内部血管分布弥散，一般不形成包绕，无明显的增生血管网，走形与正常的子宫动脉相同[8]。因此，在超声造影早期，子宫肌瘤假包膜血管环状灌注首先表现为环状高增强，造影剂随分支呈放射状进入瘤体内部，达峰时整个瘤体呈均匀性或不均匀性高增强。造影剂消退时，假包膜血管网内造影剂停留时间较长，出现子宫肌瘤在造影消退时表现为周边环状稍高增强，内部呈低增强，与周边肌层有明显边界[9]。子宫腺肌症在造影早期表现为包块内短线状增强，达峰时呈不均匀性高增强；造影消退时，子宫腺肌症内消退较周边肌层快而呈低增强，与周边肌层无明显分界[10]。子宫肌瘤与子宫腺肌症在静脉超声造影检查时具有以上各自特征性改变，可以弥补常规超声不能显示微循环血流灌注情况的不足，从而提高两者之间的鉴别诊断准确率，为临床提供可靠的诊断依据。
同时，超声造影在鉴别子宫肌瘤良性变性与恶性变性较常规超声更具临床意义。子宫肌瘤良性变性主要包括玻璃样变，即肌瘤的部分组织出现水肿变软，被透明的组织取代；囊性变主要为在玻璃样变的基础上组织继续坏死，液化形成囊腔；此外还有钙化，脂肪样变，红色样变（该型主要见于妊娠期及产褥期）。良性变性超声造影具有子宫肌瘤造影特征性表现，周边呈环状及半环状增强，与周边肌层分界清，内部可表现为低增强或无造影剂灌注[11]。子宫肉瘤是来源于子宫间质、结缔组织或平滑肌的一类恶性肿瘤，临床少见，约占妇科恶性肿瘤的1%～3%[12]。常规超声一般声像图无特征性改变，易误诊。静脉超声造影显示肉瘤样变包块内部造影剂灌注可见粗大血管供应，造影模式呈快进快退高增强，由于肿瘤组织向周边侵袭，病变周边与正常子宫肌层间分界不清，可为临床提高治疗依据[13]。子宫肌瘤在临床的治疗方法主要有保守治疗，手术肌瘤剔除或子宫切除。近年来高强度聚焦超声（HIFU）治疗，微波消融治疗，子宫动脉栓塞治疗等微创手术治疗子宫肌瘤在临床运用日益广泛，因微创手术创伤小，可以保留子宫成为一种新兴治疗手段，更为患者接受。过去，MRI常被用做评价HIFU治疗子宫肌瘤的一种检查方法，研究发现通过超声造影实时动态全程观察包块内部的血供情况，从而判断HIFU治疗子宫肌瘤的疗效及预后，较MRI检查更加直观经济快捷[14]。临床通过子宫动脉栓塞阻断或减少子宫肌瘤的血供，使子宫肌瘤体积缩小，也取得显著的疗效。超声造影在评价子宫动脉栓塞治疗肌瘤后疗效也具有很大的临床价值，栓塞治疗前后可以对比观察子宫肌瘤内部及周边造影剂灌注情况从而判断疗效及预后，也可以做为术后随访的常规检查方法[15]。但超声造影检查也有一定的局限性，比如最常见的取样容积有限，无法对多个部位的病变进行同时观察，可能需进行多次造影检查[16]。造影剂注入量和速度会影响图像显示效果；造影过程中，超声探头需固定，对于肥胖气体较多患者，也会影响造影图像质量[17]。当然，对于病灶的定量分析笔者可以通过时间-强度分析软件分析，可获得准确的数据，从而避免人为主观因素的影响。
综上所述，静脉超声造影在子宫肌瘤与子宫腺肌症的鉴别诊断中具有重要临床价值[18]。在评价微创手术治疗子宫肌瘤疗效及预后较传统MRI检查更具优势，在鉴别子宫肌瘤良性变性与肉瘤样恶性病变中较常规超声更具价值，该项技术值得在临床广泛应用开展。
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