[名词解释]
儿茶酚胺增多症(hypercatecholaminemia):由于肾上腺嗜铬细胞瘤、副神经节瘤(肾上腺外嗜铬细胞瘤)与肾上腺髓质增生的共同特点是肿瘤或肾上腺髓质的嗜铬细胞分泌过量的儿茶酚胺(肾上腺素、去甲肾上腺素和/或多巴胺),而引起相似的临床症状,统称为儿茶酚胺增多症。
嗜铬细胞瘤( pheochromocytoma,PHEO ):起源于肾上腺髓质嗜铬细胞的肿瘤,合成、存储和分解代谢儿茶酚胺,并因后者的释放引起症状。
副神经节瘤(paraganglioma,PGL):起源于肾上腺外的嗜铬细胞的肿瘤,包括源于交感神经(腹部、盆腔、胸部)和副交感神经(头颈部)者。前者多具有儿茶酚胺激素功能活性,而后者罕见过量儿茶酚胺产生。
2004年,WHO的内分泌肿瘤分类[1]将嗜铬细胞瘤定义为来源于肾上腺髓质的产生儿茶酚胺的嗜铬细胞的肿瘤,即肾上腺内副神经节瘤;而将交感神经和副交感神经节来源者定义为肾上腺外副神经节瘤。目前比较统一的观点是嗜铬细胞瘤特指肾上腺嗜铬细胞瘤,而将传统概念的肾上腺外或异位嗜铬细胞瘤统称为副神经节瘤。
恶性嗜铬细胞瘤( malignant pheochromocytoma):WHO的诊断标准[1]是在没有嗜铬组织的区域出现嗜铬细胞(转移灶)如骨、淋巴结、肝、肺等。局部浸润和肿瘤细胞分化程度均不能用于区分嗜铬细胞瘤的良恶性。
一、流行病学和病因学
嗜铬细胞瘤/副神经节瘤(pheochromocytoma / paraganglioma,PHEO/PGL)占高血压病人的0.1%~0.6%[2-4],年发病率3~4 / 100万人,尸检发现率约为0.09%~0.25%,人群中约50~75%的PHEO/PGL未被诊断[5]。目前约25%的PHEO系影像学偶然发现,占肾上腺偶发瘤的4%~5%[6]。男女发病率无明显差别,可以发生于任何年龄,多见于40~50岁。PGL占全部嗜铬细胞肿瘤的15%~24%[7, 8]。
PHEO/PGL病因尚不明,可能与遗传有关。近年研究表明约30%有家族遗传背景,并已明确致病基因:Von Hippel-Lindau 病(VHL病)(VHL基因突变)、多发内分泌肿瘤-1型(MEN-1)(MEN1基因突变)、多发内分泌肿瘤-2型(MEN-2)(RET基因突变)、家族性PHEO-PGL综合征(SDHD、SDHB 或 SDHC 基因突变)、神经纤维瘤病-1型(NF-1基因突变)[8, 9]。成人散发性PHEO/PGL基因突变率约24%[10],儿童可达36%[11]。
PHEO/PGL的发生率在 MEN-2为70%~80%[12],VHL病约10%[13],NF-1约3%~5%[14, 15]。
二、病理和病理生理
PHEO/PGL主要源于肾上腺髓质,约9%~24%源于肾上腺外[16, 17]。PHEO多为单侧,但遗传性者常为双侧、多发,如MEN-2相关者约 50%~80%为双侧。约95%以上的PGL位于腹部和盆腔[18],最常见部位为腹主动脉旁、肾门附近、下腔静脉旁等;其次为盆腔,膀胱PGL占膀胱肿瘤0.5%,占PGL的10%[19];再次为头颈和胸腔纵隔。15%~24%可多发[15, 20, 21]。
典型PHEO直径约 3~5 cm大小,但也可>10 cm,平均重量40~100 g (<5 ~>3500 g)。2004年WHO的肾上腺肿瘤的组织分类将嗜铬细胞相关肿瘤分为肾上腺髓质肿瘤和肾上腺外副神经节瘤两大类:前者包括良、恶性PHEO和混合型PHEO/PGL;后者包括肾上腺外交感神经和副交感神经PGL等。恶性PGL发生率约30%~40%[7, 8],肾上腺恶性PHEO约10%。儿童多发和肾上腺外者占30%~43%[22, 23],其中恶性者占26%~35%[20, 24]。转移部位多见于淋巴结、肝、肺、骨等器官。但病理组织学特征本身不能预测恶性或转移[1]。
PHEO/PGL主要分泌儿茶酚胺(CA)如NE和E(前者为主),极少可分泌多巴胺。CA、交感神经系统以及α-、β-受体下调和敏感性的降低等多种因素参与维持其血流动力学变化。PHEO/PGL还可分泌其他激素或多肽如ACTH、血管活性肠肽、神经肽Y、心房利钠素、生长激素释放因子、生长抑素、甲状旁腺素相关肽、白细胞介素-6等而引起不同的病理生理和临床表现[25-27]。
三、临床表现
高血压是最常见的临床症状,发生率约80%~90%[28]。50%~60%为持续性,40%~50%为发作性,10%~50%可出现体位性低血压,5%血压正常。可伴有典型的头痛、心悸、多汗“三联征”,其发生率为50%以上[29]。伴有血糖增高的发生率约40%。
部分患者可能会以心肌病、高钙血症、血尿、糖尿病、库欣综合征、肠梗阻、甚至视力下降等原因就诊[30];家族性PHEO/PGL可以相关综合征的临床症状和体征为主要表现:如MEN-2(甲状腺髓样癌、甲状旁腺功能亢进症、多发粘膜神经瘤)、VHL病(视网膜和中枢神经系统血管母细胞瘤、肾囊肿或肾细胞癌、胰腺囊肿或肿瘤、附睾囊腺瘤)、NF-1(皮肤多发神经纤维瘤、色斑、虹膜“利舍结节”)、家族性PHEO-PGL综合征(头颈部副交感神经副神经节瘤、嗜铬细胞瘤、交感神经副神经节瘤)等[2, 5, 31, 32]。约15%可及腹部肿块[33]。
少见情况以急症形式出现[34]:如高血压危象、休克、急性心衰、肺水肿、心肌梗死、严重心律失常、急性肾功能不全、高热等。
PHEO在肾上腺偶发瘤的发生率约5%[35]。约有8%的患者无任何症状,多见于家族性发病者或瘤体巨大的囊性PHEO[30]。
四、诊 断
PHEO/PGL的诊断主要是根据临床表现对可疑病人的筛查、定性诊断、影像解剖和功能定位诊断等,对于有遗传倾向者尚需基因筛查。
(一)可疑病例的筛查指征:
(1)伴有头痛、心悸、大汗等“三联征”的高血压;
(2)顽固性高血压;
(3)血压易变不稳定者;
(4)麻醉、手术、血管造影检查、妊娠中血压升高或波动剧烈者,不能解释的低血压;
(5)PHEO/PGL家族遗传背景者;
(6)肾上腺偶发瘤;
(7)特发性扩张性心肌病。
(二)定性诊断
实验室测定血浆和尿的游离CA(E、NE、DA)及其代谢产物如VMA是传统诊断PHEO/PGL的重要方法。肿瘤CA的释放入血呈“间歇性”,直接检测CA易出现假阴性[36]。但CA在瘤细胞内的代谢呈持续性,其中间产物甲氧基肾上腺素类物质(metanephrines,MNs)以“渗漏”形式持续释放入血[37],血浆游离MNs和尿分馏的甲氧肾上腺素(urinary fractionated metanephrines)的诊断敏感性优于CA的测定[36, 38-40]。MNs包括甲氧基肾上腺素(MN)和甲氧基去甲肾上腺素(NMN),进入循环的MNs为游离形式,主要来源于PHEO/PGL肿瘤细胞,经消化道、脾、胰的相关酶修饰为硫酸盐结合的MNs,消化道等本身也可合成大量的硫酸盐结合的NMN,故结合型MNs特异性略差。
1.24小时尿CA(推荐) 仍是目前定性诊断的主要生化检查手段[41]。敏感性84%,特异性81%,假阴性率14%[30]。结果阴性而临床高度可疑者建议重复多次和/或高血压发作时留尿测定,阴性不排除诊断。
2.血浆游离MNs(推荐) 包括MN和NMN。敏感性97%~99%,特异性82%~96%,适于高危人群的筛查和监测。阴性者几乎能有效排除PHEO/PGL,假阴性率仅1.4%[40],无症状的小肿瘤或仅分泌多巴胺者,可假阴性[8, 42, 43]。国内仅有少数单位开展,建议推广。
3.24h尿分馏的MNs(推荐) 须经硫酸盐的解离步骤后检测,故不能区分游离型与结合型,为二者之和。但可区分MN和NMN。特异性高达98%,但敏感性略低,约69%,适于低危人群的筛查[42]。
4.24h尿总MNs(MN+NMN)(可选) 敏感性77%,特异性93%。
5. 24h尿VMA(可选) 敏感性仅46%~67%,假阴性率41%,但特异性高达95%[16]。
6.血浆CA(可选) 检测结果受多种生理、病理因素及药物的影响。
血浆游离MNs和尿分馏的MNs升高≥正常值上限4倍以上,诊断PHEO/PGL的可能几乎100%[44]。临床疑诊但生化检查结果处于临界或灰区者应标化取样条件,推荐联合检测以提高准确率。曾经有可乐定抑制试验及胰高糖素激发试验等用以诊断和鉴别PHEO/PGL,但由于心、脑血管意外风险等可能,国内已基本摒弃。
(三)定位诊断
包括解剖影像学和功能影像学[36]。
1.解剖影像学定位 主要是 CT 和 MRI。二者具有类似的诊断敏感性(90%~100%)和特异性(70%~80%),没有证据表明何者更优,可选其一[36, 45, 46]。对PHEO的敏感性优于PGL、转移、复发病灶,但排除PHEO/PGL的特异性仅约50%。推荐 CT/MRI 的初始扫描范围为腹部+盆腔,目的在于检出肾上腺和/或肾上腺外多发病变,如为阴性,扫描胸部和头颈[36, 47]。
(1) CT 平扫 + 增强(推荐首选):优点是价格适中、敏感性高、扫描时间短。可发现肾上腺 0.5 cm和肾上腺外 1.0 cm以上的 PHEO/PGL。肿瘤内密度不均和显著强化为其特点,能充分反映肿瘤形态特征及与周围组织的解剖关系[48]。
(2) MRI(推荐):优点是敏感性与CT相仿、无电离辐射、无造影剂过敏之虞。PHEO/PGL 血供丰富,T1WI 低信号、T2WI 高信号,反向序列信号无衰减为其特点。推荐以下情况代替CT作为首选定位或补充检查[36, 49]:
1)儿童、孕妇或其他需减少放射性暴露者;
2)对CT造影剂过敏者;
3)生化证实儿茶酚胺升高而 CT 扫描阴性者;
4)肿瘤与周围大血管关系密切,评价有无血管侵犯。
5)全身 MRI 弥散加权成像(DWI)有助于探测多发或转移病灶。
(3)超声检查(可选择):敏感性低,但因其简便、无创、价格低廉,可作为初筛检查,特别是可疑颈部PGL以及婴幼儿、孕妇等[5, 47]。但不推荐用于定位。
2.功能影像学定位(推荐有条件的地区选择)
不作一线推荐[50]。功能影像检查的价值和指征[51, 52]:
1)确诊定位并利于鉴别诊断。
2)检出多发或转移病灶(分泌E的PHEO>5cm;分泌NE的PHEO;功能性PGL)。
3)生化指标阳性和/或可疑,CT / MRI 未能定位者。
4)术后复发者。
(1)间碘苄胍(metaiodobenzylguanidine,MIBG)显像:MIBG为去甲肾上腺素类似物,能被嗜铬细胞儿茶酚胺囊泡摄取[47]。 131I-MIBG和123I-MIBG可同时对PHEO/PGL进行形态解剖和功能的定位,二者特异性均达95%~100% ,灵敏度分别为77%~90% 和 83%~100%[53, 54];但对PGL和恶性PHEO敏感性较低(71%和56%)[55, 56]。假阳性罕见于肾上腺皮质癌[57]和某些感染性疾病如放线菌病[58];假阴性见于某些药物影响(如三环类抗抑郁精神病药、钙拮抗剂、可卡因等)和肿瘤坏死或去分化[59]。
MIBG显像前必须使用卢戈氏液,5滴 3次/日×3天,封闭甲状腺。
(2)生长抑素受体(somatostatin receptor)显像:生长抑素受体为G蛋白偶联的跨膜蛋白,有5种亚型。PHEO / PGL主要表达2和4型(约73%)[60]。奥曲肽为生长抑素类似物,与生长抑素受体的亲和性依次为2、5、3型[61]。111In-DTPA-奥曲肽显像敏感性不及MIBG,MIBG阳性的PHEO/PGL仅25%~34%奥曲肽阳性,但对恶性/转移性病灶的敏感性优于MIBG(87% 和 57%)[53]。
(3)PET显像:18F-FDG-PET、11C-对羟基麻黄碱-PET、11C-肾上腺素-PET、18F-DOPA-PET和18F-DA-PET均有报道用于PHEO/PGL的定位诊断,但前3者特异性差, 18F-DA-PET优于MIBG,敏感性和特异性达100%[62, 63]。
(四)遗传性综合征的诊断和基因筛查
1. 大约1/3的PHEO/PGL有遗传因素参与[64] [2, 5, 31, 32]。遗传性综合征和基因筛查的价值在于:
(1)主动监测肿瘤复发或多发;
(2)及早发现其他受累系统病变;
(3)监测无症状的亲属,早期发现肿瘤;
(4)致命性肿瘤的预防如RET突变患儿的甲状腺预防性切除。
2. 下列情况应考虑遗传疾病[7, 65]
(1)PHEO/PGL家族史者;
(2)双侧、多发或肾上腺外PHEO;
(3)年轻患者(<20岁);
(4)患者及其亲属具有其他系统病变:脑、眼、甲状腺、甲状旁腺、肾、颈部、胰腺、附睾、皮肤等。
3. 筛查内容包括
(1)家族史的问询。
(2)系统临床体征和辅助检查:皮肤病变(NF-1);甲状腺病变和血降钙素升高(MEN-2);影像学检查肾脏、胰腺、其他腹部肿瘤,术前常规眼底视网膜检查、脑脊髓MRI检查(VHL)。
(3)基因筛查(可选择):RET/VHL/SDHB/SDHD,若阳性,一级亲属遗传咨询。
五、治 疗
(一)术前药物准备
PHEO/PGL术前充分的准备是手术成功的关键[66],未常规予α-受体阻滞剂以前PHEO手术死亡率达24%~50%[67-69],充分的药物准备可使手术死亡率低于3%[70, 71]。术前药物准备的目标[72]在于阻断过量CA的作用,维持正常血压、心率/心律,改善心脏和其他脏器的功能;纠正有效血容量不足;防止手术、麻醉诱发CA的大量释放所致的血压剧烈波动,减少急性心衰、肺水肿等严重并发症的发生[67]。
1.控制高血压
(1)α-受体阻滞剂(推荐):最常用的是长效非选择性α-受体阻滞剂——酚苄明,初始剂量5~10 mg,2次/日,据血压调整剂量,每2~3日递增10~20 mg;发作性症状控制、血压正常或略低、体位性低血压或鼻塞出现等提示药物剂量恰当,一般每日30~60 mg 或 1 mg / kg已足[73],分3~4次口服,不超过2 mg / kg / d[74]。小儿初始剂量0.2mg / kg(<10 mg),每日4次,以0.2 mg / kg递增[75]。也可选用α1-受体阻滞剂如哌唑嗪(2~5 mg,2~3次/日)、特拉唑嗪(2~5 mg /日)、多沙唑嗪(2~16 mg /日)[76]等。压宁定(乌拉地尔)具有中枢和外周双重作用,每日30~90 mg,分次口服[77]。
服药期间饮食中增加含盐液体的摄入,以减少体位性低血压的发生,并有助扩容[74, 78]。
(2)钙离子通道阻滞剂(推荐):钙拮抗剂能够阻断NE介导的钙离子内流入血管平滑肌细胞内,达到控制血压和心率失常的目的,它还能防止CA相关的冠状动脉痉挛,有利于改善心功能[79]。其疗效几乎与α-受体阻滞剂相当,但不会引起体位性低血压[80-82]。
推荐以下3种情况联合或替代α-受体阻滞剂[18, 83]:
1)单用α-受体阻滞剂血压控制不满意者,联合应用以提高疗效,并可减少前者剂量;
2)α-受体阻滞剂严重副作用病人不能耐受者,替代之;
3)血压正常或仅间歇升高,替代α-受体阻滞剂,以免后者引起低血压或体位性低血压。
2.控制心律失常 对于CA或α-受体阻滞剂介导的心动过速(>100~120次/分)或室上性心律失常等需加用β-受体阻滞剂,使心率控制在<90次/分。但β-受体阻滞剂必须在α-受体阻滞剂使用2~3日后,因单用前者可阻断肾上腺素兴奋β2受体扩张血管的作用而可能诱发高血压危象、心肌梗死、肺水肿等致命的并发症[84]。推荐心选择性的β1-受体阻滞剂如阿替洛尔、美托洛尔等[72]。
3.高血压危象的处理 推荐硝普钠、酚妥拉明或尼卡地平静脉泵入[84]。
4.术前药物准备的时间和标准 推荐至少10~14天[5],发作频繁者需4~6周。以下几点提示术前药物充分[8, 77, 85]:
1)血压稳定在120/80 mmHg左右,心率<80~90次/分;
2)无阵发性血压升高、心悸、多汗等现象;
3)体重呈增加趋势,红细胞压积<45%;
4)轻度鼻塞,四肢末端发凉感消失或有温暖感,甲床红润等表明微循环灌注良好。
(二)手术治疗
手术切除是PHEO/PGL最有效的治疗方法。强调与麻醉科等多学科充分合作。推荐全麻,实时监测动脉血压和中心静脉压,必要时漂浮导管。积极扩容的同时注意防治心力衰竭。
1.手术方式 根据病情、肿瘤的大小、部位及与周围血管的关系和术者的经验合理选择开放性手术或腹腔镜手术。
(1)腹腔镜手术(推荐):与开放手术相比,腹腔镜嗜铬细胞瘤切除术具有术中CA释放少、血压波动幅度小、创伤小、术后恢复快、住院时间短等优点,是肾上腺PHEO推荐首选的手术方式[86-89]。其选择主要决定于肿瘤的大小和术者的经验[90]。但肿瘤大小并非绝对限制[91, 92],多数学者[93]推荐肿瘤<6 cm。经腹和经腹膜后途径没有显著差异,但后者术后恢复快[94]。
(2)开放手术:推荐于肿瘤巨大、疑恶性、肾上腺外PGL、多发需探查者。腹主动脉主干及肠系膜上动脉区有丰富的副神经节嗜铬体,为肿瘤的好发部位,是探查的主要区域;对来自胸腔、纵隔或膀胱的PGL,应根据肿瘤位置,选择相应手术径路。肿瘤分离有困难者可行包膜内剜除。膀胱PGL有恶性倾向,推荐根据肿瘤部位和大小行膀胱部分或全膀胱切除术。
对定性诊断不明确的肿物,手术探查需在α-受体阻滞剂充分准备后进行。
2.肾上腺保留与否 推荐尽可能保留肾上腺,特别是双侧、家族性或具有遗传背景者推荐保留正常肾上腺组织,基于如下原因[95-99]:避免皮质激素终生替代、家族性PHEO恶性罕见(2%)[100]、残留肾上腺复发率低(10%~17%)[6]。
3.术后处理 ICU监护24~48小时,持续的心电图、动脉压、中心静脉压等监测,及时发现并处理可能的心血管和代谢相关并发症。术后高血压[51]、低血压、低血糖较常见,应常规适量扩容和5%葡萄糖液补充,维持正平衡[8]。
(三)恶性PHEO/PGL的治疗
多种病理学指标用于预测PHEO/PGL的恶性行为,但迄今最具预测价值的是定位于肾上腺外(36%)[101]、肿瘤的大小(>5cm者76%,≤5cm者24%)和 SDHB 基因突变(66%~83%)[16, 32, 102]。血、尿多巴胺和去甲肾上腺素水平显著升高亦提示恶性可能[103, 104]。
1.手术治疗(推荐) 手术切除原发或转移病灶仍是主要治疗手段[105]。手术减瘤虽不能延长生存,但有助控制血压等相关症状,并可能有利于术后放化疗或核素治疗[36]。
2.放射性核素治疗 用于无法手术或多发转移、MIBG或奥曲肽显像阳性者。最常用的药物是131I-MIBG,其治疗效应与每克肿瘤组织吸收剂量和肿瘤体积密切相关,肿瘤直径应小于2cm以保证131I-MIBG的良好摄取。大剂量131I-MIBG 治疗能延长生存,缓解症状[106];短期内效果良好,症状有效率75%,激素有效率45%,肿瘤体积部分缓解率30%,完全缓解率5%[106, 107]。但长期疗效欠佳,2年内几乎均有复发或转移。主要副作用是骨髓抑制。核素标记的奥曲肽可用于MIBG阴性者,但疗效尚难评价。
3.放疗和化疗 外放射治疗推荐于无法手术切除的肿瘤和缓解骨转移所致疼痛,但可能加重高血压[108]。化疗推荐 CVD 方案(环磷酰胺、长春新碱、氮烯唑胺),有效率约50%,但多于2年内复发[109, 110]。联合MIBG可能提高疗效[111]。抗血管生成靶向药物治疗可能有效[102, 112-116]。
4. 处理儿茶酚胺增多症 对于恶性或因故不能手术者推荐α-受体阻滞剂、β-受体阻滞剂控制高血压[8]。
六、预后和随访
(一)预后
PHEO/PGL的预后与年龄、良恶性、有无家族史及治疗早晚等有关。良性者5年生存率>95%,但约50%患者仍持续高血压[117]。复发率为6.5%~17%,复发者恶性率约50%,家族性、肾上腺外及右侧者更易复发[6]。恶性PHEO/PGL不可治愈,5年生存率约 50%[102],肝、肺转移较骨转移者预后差[46, 102],其中约50%死于1~3年,但约50%可存活20年以上[84]。
(二)随访
1.随访原因
(1)肿瘤有无残留;
(2)病理难于鉴别良恶性,主要依据其临床出现转移;
(3)易复发、多发,特别是家族发病者。
2.随访内容:包括临床症状(如高血压)、生化指标(如血浆游离MNs、24h尿CA和分馏的MNs)、CT扫描等。
3.随访方案
(1)推荐术后10~14天复查血尿生化指标[36, 118],判断肿瘤是否残留、有无转移等。
(2)散发病例单侧肾上腺切除者每年一次,至少连续10年[117]。
(3)高危群体(SDHB突变、PGL、肿瘤体积巨大)和遗传性PHEO/PGL者每6~12个月复查1次临床和生化指标,终生随访[119]。
七、PHEO/PGL诊断流程图[29, 30, 120, 121]
无肿物 |
肿 物 |
胸部及头颈CT / MRI |
无肿物 |
肿 物 |
排除PHEO / PGL |
MIBG/奥曲肽/PET |
- |
+ |
影像功能定位 ● MIBG ● 奥曲肽显像 |
+ |
PHEO / PGL |
基因筛查(可选) |
+ |
- |
PET |
- |
重复生 化检查 |
生化检测≥2次 ● 血浆游离MN、NMN ● 24h尿MN、NMN ● 24h尿CA |
临 界 |
升高>2倍 |
正 常 |
生化证实 |
重复生化检查 |
症状依旧或高危 |
+ |
+ |
- |
- |
影 像 解 剖 定 位 (腹部+盆腔CT / MRI) |
6月后重复生化检查 |
症状依旧 |
排除PHEO / PGL |
- |
+ |
嗜铬细胞瘤/副神经节瘤(PHEO/PGL) |
良 性 |
恶 性 |
肾上腺 |
肾上腺外 |
原发局限病灶 |
转移病灶 |
单 侧 |
双 侧 |
能否“根治”切除? |
+ |
- |
可切除 |
不可切除 |
散发性 |
遗传性 |
原发灶+转移灶切除 |
减瘤手术 |
肿瘤切除 |
保留肾上腺的肿瘤切除 |
肿瘤切除 |
“根治”切除 |
减瘤切除 |
● 131I-MIBG (a) ● 奥曲肽 (b) ● 化疗 ● 放疗 |
131I-MIBG (a) |
终生随访 |
随访≥10年 |
(a)MIBG显像阳性者(b)奥曲肽显像阳性者 |
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