Abstract
目的
分析散发嗜铬细胞瘤和副神经节瘤(pheochromocytoma and paraganglioma, PPGL)患者中血浆游离型甲氧基肾上腺素类物质(metanephrines, MNs)正常者的临床特点, MNs已作为PPGL的首选检测方法在临床中广泛应用, MNs正常的PPGL较少见。
方法
选择2015年3月—2020年1月于北京大学第一医院行泌尿外科手术, 病理确诊为PPGL的散发患者共104例, 所有患者均有术前血浆游离型MNs检测结果, 其中8例(7.69%)MNs正常。回顾MNs正常患者的就诊原因, 临床表现, 术前检测血浆游离型MNs、3-甲氧基酪胺(3-methoxytyramine, 3-MT)、血儿茶酚胺和嗜铬粒蛋白A(chromograninA, CgA)的结果, 影像学表现, 术前诊断, 术前用药准备, 术中血压波动情况及肿瘤组织病理学特点, 并与同期MNs升高的PPGL患者相比较。对MNs正常患者进行术后随访。
结果
MNs正常的8例PPGL患者中, 最常见的临床症状为多汗(3/8)、腰腹痛(3/8)、头痛(2/8)、心悸(2/8)和疲乏(2/8)。对比MNs正常组和升高组患者的其他生化检验结果, 血3-MT、儿茶酚胺诊断阳性率组间差异无统计学意义, 血浆CgA诊断阳性率在MNs正常组显著下降(2/5 vs.41/43, P=0.005)。两组患者增强CT出现典型表现的比例差异无统计学意义。在8例MNs正常患者中, 6例因明确的PPGL既往史, 或典型的症状及CT表现, 3-MT、CgA升高, PET-CT阳性等原因诊断为PPGL, 2例误诊为无功能腺瘤或原发性醛固酮增多症。全部MNs正常患者均应用α受体阻滞剂术前准备, 其中1例出现术中平均动脉压 < 60 mmHg。8例术后随访的中位时间为1.5(0.5~4.5)年, 增强CT检查均未见新发肿瘤证据。2例MNs正常患者术后复查3-MT和(或)CgA降至正常。
结论
对于出现PPGL典型症状的肾上腺或腹膜后肿瘤患者及有PPGL既往史患者, MNs检测正常不能作为排除PPGL的充分依据。血3-MT、儿茶酚胺、CgA及影像学检查或对PPGL的诊断有帮助。怀疑MNs正常的PPGL患者推荐应用α受体阻滞剂术前准备, 但应避免过量。MNs正常患者的术后随访应重点监测术前阳性的生化指标。
Keywords: 嗜铬细胞瘤, 副神经节瘤, 甲氧基肾上腺素类物质, 诊断
Abstract
Objective
Plasma free metanephrines (MNs) have been widely used as an initial test for pheochromocytoma and paraganglioma (PPGL). PPGL without MNs elevation has been reported on rare occasions. The objective of this study was to analyze the clinical profile of sporadic PPGL patients with normal MNs.
Methods
In the study, 104 patients with sporadic PPGL diagnosed by histopathology in Peking University First Hospital from March 2015 to January 2020 were enrolled. All the patients had plasma MNs result, of whom, eight (7.69%) were with normal MNs. The reasons for their medical visits, clinical manifestations, the levels of plasma free MNs, 3-methoxytyramine (3-MT), catecholamines and chromogranin A (CgA), and the imaging findings were documented. Their preoperative diagnosis, perioperative medical management, and intraoperative blood pressure were analyzed. All the data mentioned above were compared with the MNs elevated group. The postoperative follow-up for MNs normal patients were applied.
Results
For the eight PPGL patients with normal plasma MNs, the most common clinical symptoms were sweating (3/8), abdominal and back pain (3/8), headache (2/8), palpitations (2/8), and fatigue (2/8). There were no significant differences in plasma free 3-MT and catecholamines' diagnostic positive rate between the MNs normal group and MNs elevated group, but the rate for plasma CgA was significantly decreased in the MNs normal group (2/5 vs. 41/43, P=0.005). No significant difference was found for the incidence of typical findings by enhanced CT between the two groups. In these eight MNs normal patients, six were diagnosed with PPGL by the previous history of PPGL, typical symptoms and CT findings, or elevation of 3-MT, CgA levels or positive results of PET-CT; two patients were misdiagnosed as nonfunctioning adenoma or primary aldosteronism. All these MNs normal patients underwent preoperative management with alpha adrenergic receptor blockers, of whom, one had an average intraoperative arterial pressure < 60 mmHg during surgery. The median follow-up time for the eight patients was 1.5 (0.5－4.5) years. No evidence of new tumors was found on the enhanced CT scans. Two MNs normal patients' plasma 3-MT and (or) CgA decreased to normal.
Conclusion
For patients with adrenal or retroperitoneal tumors, typical symptoms or a previous history of PPGL, normal plasma MNs is not a sufficient exclusion for PPGL. Plasma 3-MT, catecholamine, CgA results and the imaging findings are helpful for the diagnosis of PPGL. We recommend patients with suspected MNs normal PPGL take alpha adrenergic receptor blockers as preoperative blockade, but should avoid overdose. Postoperative follow-up for patients with normal MNs should focus on the positive biochemical markers before surgery.
Keywords: Pheochromocytoma, Paraganglioma, Metanephrines, Diagnosis
血浆游离型甲氧基肾上腺素(metanephrine, MN)和血浆游离型甲氧基去甲肾上腺素(normetanephrine, NMN)合称为血浆游离型甲氧基肾上腺类物质(metanephrines, MNs)。绝大部分的MNs在肾上腺髓质及嗜铬细胞瘤和副神经节瘤(pheochromocytoma and paraganglioma, PPGL)的瘤体内代谢生成, 并可在人体血液中以高浓度水平持续存在。大量前瞻性及回顾性研究显示, 血MNs对PPGL的诊断敏感度高达95%~100%[1-5]。目前, 临床上已将血MNs作为PPGL的首选生化检测指标、手术成功评价指标及术后随访指标[6-8]。
血MNs检测正常的PPGL较为少见, 该类PPGL极易被漏诊或误诊, 因此可能导致患者未能及时手术, 或在术前未行充分的药物准备。有部分报道显示, 血多巴胺的中间代谢产物血浆游离型3-甲氧基酪胺(3-methoxytyramine, 3-MT)和血浆嗜铬粒蛋白A(chromograninA, CgA)等生物标志物在血MNs正常的PPGL患者中可能升高[8-9], 典型的影像学表现及功能影像学检查或有助于该类PPGL患者的确诊[10]。本研究旨在回顾北京大学第一医院近5年来血MNs正常患者的临床表现, 总结血浆游离型3-MT、血儿茶酚胺、血CgA等生化指标以及影像学检查对该类PPGL患者的诊断意义, 以期提高临床医生对该病的认识。
1. 资料与方法
1.1. 研究对象
本研究回顾了2015年3月—2020年1月于北京大学第一医院行手术, 经病理明确诊断为PPGL的患者共219例, 排除无术前血浆游离型MNs检测结果患者97人, 符合PPGL相关遗传综合征表现或经基因检查确诊为PPGL相关遗传综合征者18人。共入组具有完整病例资料及术前血浆游离型MNs检测结果的散发型PPGL患者104例, 其中MNs正常者8例, MNs升高者96例。
1.2. 研究方法
根据北京大学第一医院电子病历系统, 收集入组对象性别、起病年龄、就诊原因、临床症状、血压情况, 记录患者术前血MNs、3-MT、儿茶酚胺、CgA水平、CT及其他功能影像学检查结果, 分析MNs正常患者术前诊断、术前用药及术中血压波动情况。对MNs正常患者进行术后随访, 随访时间为0.5~4.5年。本研究高血压的诊断标准为在未服用降压药物情况下收缩压≥140 mmHg和(或)舒张压≥90 mmHg。手术中血压波动的标准为患者术中血压出现收缩压>200 mmHg, 或平均动脉压 < 60 mmHg[11]。
应用液相色谱-串联质谱法(liquid chromatography-tandem mass spectrometric, LC-MS)检测血MNs、3-MT和血儿茶酚胺。参考范围分别为:MN≤0.50 nmol/L, NMN≤0.90 nmol/L, 3-MT < 0.18 nmol/L; 肾上腺素(epinephrine, E)0.05~1.39 pmol/L, 去甲肾上腺素(norepinephrine, NE)0.51~3.26 pmol/L, 多巴胺(dopamine, DA)0.07~0.68 pmol/L。LC-MS检测血MNs和3-MT的精密度分别为:MN 2.4%~2.7%, NMN 2.2%~2.6%, 3-MT 2.4%~3.6%;线性范围:MN 0.080~14.231 nmol/L, NMN 0.080~14.324 nmol/L, 3-MT 0.080~9.110 nmol/L; 准确度(采用澳大利亚皇家病理学院室间质评评估):MN 3.6%~6.2%(接受范围为±15%), NMN 4.7%~9.0%(接受范围±20%), 3-MT 6.5%~13.9%(接受范围±30%)。LC-MS检测血儿茶酚胺的精密度:E 2.5%~3.6%, NE 4.0%~9.0%, DA 2.3%~4.2%;线性范围:E 8~1 024 nmol/L, NE 8~1 024 nmol/L, DA 16~2 056 nmol/L; 准确度(采用加标回收率评估):E 86.9%~113.3%, NE 85.7%~111.9%, DA 93.9%~114.2%(接受范围为85%~115%)。应用放射免疫法检测CgA的正常范围为19.4~98.1 μg/L, 其批内变异系数为2.2%~6.0%, 批间变异系数为5.3%~8.5%。
MNs正常定义为血MN、NMN均在正常范围内, 儿茶酚胺正常定义为血E、NE和DA均在正常范围内, PPGL的典型增强CT表现定义为肾上腺内/外出现明显不均匀强化的占位, 功能性影像学检查阳性定义为相关造影剂摄取阳性。
1.3. 统计学分析
应用SPSS 21.0软件, 符合正态分布的计量资料以均值±标准差表示, 非正态分布的计量变量以中位数(范围)表示, 分类变量以比例表示。两组间比较, 符合正态分布的计量变量应用t检验, 不符合正态分布的计量变量应用Mann-Whitney U检验, 连续校正卡方检验用于比较理论数T＜5但T≥1的分类变量的组间差异, Fisher确切概率法用于比较理论数T＜1的分类变量的组间差异。P < 0.05认为差异具有统计学意义。
2. 结果
2.1. MNs正常PPGL患者的临床特点
在104例散发PPGL患者中, MNs正常患者共8例(表 1、表 2), 占7.69%, 确诊PPGL时的中位年龄为55(23~70)岁。8例MNs正常者中男性2例, 女性6例; 嗜铬细胞瘤6例, 副神经节瘤2例; 初发患者6例, 复发患者2例, 其中1人合并肾转移(表 1, 患者8)。对比MNs升高组, MNs正常组中复发患者占比更高(2/8 vs. 2/96, P=0.029), 患者年龄、性别、肿瘤位置等在两组间差异均无统计学意义(表 3)。
1.
血浆游离型MNs正常的PPGL患者的临床特点
Clinical features in PPGL patients with normal plasma free MNs
| Case | Gender | Age/years | Reasons for consultation | Symptoms | Hypertension | BMI/(kg/m2) | Tumor location | Tumor diameter/cm | Typical findings on enhanced CT | Functional imaging | Preoperative laboratory test | ||
| MN/(nmol/L) | NMN/(nmol/L) | 3-MT/(nmol/L) | |||||||||||
| MNs, metanephrines; NMN, normetanephrine; BMI, body mass index; PPGL, pheochromocytoma and paraganglioma; 3-MT, 3-methoxytyramine; F, female; M, male; ND, not done; 99mTc-TOC, 99mTc-octreo-tide; PET, positron emission tomography; MIBG, 123I-metaiodobenzylguanidine. Reference interval：MN≤0.50 nmol/L, NMN≤0.90 nmol/L, 3-MT＜0.18 nmol/L. | |||||||||||||
| 1 | F | 40 | Follow-up after surgery | Fatigue | Persistent | 26.24 | Adrenal | 1.5 | No | ND | 0.11 | 0.29 | ＜0.08 |
| 2 | F | 70 | Typical symptoms | Sweating, dizziness, fatigue | Persistent | 24.88 | Adrenal | 1.5 | No | PET-CT (+) | 0.20 | 0.50 | ＜0.08 |
| 3 | F | 62 | Typical symptoms | Palpitations, sweating, abdominal pain | Paroxysmal | 27.85 | Retroperitoneal | 5 | Yes | ND | 0.22 | 0.59 | ＜0.08 |
| 4 | M | 66 | Typical symptoms | Headache, palpitations, sweating | Persistent | 26.30 | Retroperitoneal | 1.2 | No | ND | 0.19 | 0.71 | ＜0.08 |
| 5 | F | 25 | Typical symptoms | Headache, nausea | Paroxysmal | 22.56 | Adrenal | 4.5 | Yes | ND | 0.05 | 0.20 | 2.27↑ |
| 6 | F | 23 | Adrenal incidentaloma | Asymptomatic case | Paroxysmal | 27.73 | Adrenal | 6 | Yes | 99mTc-TOC (+) | 0.03 | 0.37 | 0.23↑ |
| 7 | M | 64 | Atypical symptoms | Back pain | Paroxysmal | 23.14 | Adrenal | 5 | Yes | ND | 0.11 | 0.42 | ＜0.08 |
| 8 | F | 35 | Follow-up after surgery | Back pain | Normal blood pressure | 17.67 | Adrenal | 5.5 | Yes | PET-CT (+) MIBG (-) | 0.05 | 0.31 | ND |
2.
血浆游离型MNs正常的PPGL患者围手术期和随访资料
Perioperative management and follow-up data about PPGL patients with normal plasma free MNs
| Case | Preoperative diagnosis | Intraoperative blood pressure fluctuation | Surgical approach | Pathology | Tumor diameter/cm | Cell atypia | Mass necrosis | Ki67 | Follow-up/years | Abnormal findings on enhanced CT |
| MNs, metanephrines; PCC, pheochromocytoma; PGL, paraganglioma; PA, primary aldosteronism; PPGL, pheochromocytoma and paraganglioma. * mean arterial pressure＜60 mmHg. | ||||||||||
| 1 | PCC | No | Laparoscope | PCC | 1.5 | No | No | ＜1% | 2 | No |
| 2 | Nonfunctioning adenomas | No | Laparoscope | PCC | 1.5 | Yes | No | ＜1% | 1 | No |
| 3 | PA | No | Laparoscope | PGL | 5 | Yes | No | ＜5% | 1 | No |
| 4 | PGL | No | Laparoscope | PGL | 1.2 | No | No | ＜1% | 1 | No |
| 5 | PCC | No | Laparoscope | PCC | 4.5 | No | Yes | 20% | 4.5 | No |
| 6 | PCC | No | Laparoscope | PCC | 6 | No | No | ＜1% | 4 | No |
| 7 | PCC | Yes* | Open surgery | PCC | 5 | No | Yes | ＜1% | 3.5 | No |
| 8 | PCC | No | Open surgery | PCC | 5.5 | No | Yes | ＜1% | 0.5 | No |
3.
MNs正常与MNs升高PPGL患者临床资料的比较
Comparison of clinical data between MNs normal and MNs elevated groups in PPGL patients
| Items | All patients | MNs normal | MNs elevated | P value |
| MNs, metanephrines; PPGL, pheochromocytoma and paraganglioma; PCC, pheochromocytoma; PGL, paraganglioma; BMI, body mass index. Classic triad: headache, palpitations and sweating. | ||||
| Total, n | 104 | 8 | 96 | |
| Male/female | 49/55 | 2/6 | 47/49 | 0.349 |
| Age/years | 46(11-76) | 55(23-70) | 46(11-76) | 0.494 |
| Initial/recurrence, n/N | 100/4 | 6/2 | 94/2 | 0.029 |
| PCC/PGL, n/N | 80/24 | 6/2 | 74/22 | 1.000 |
| Metastasis, n | 4 | 1 | 3 | 0.278 |
| Symptoms, n/N | ||||
| Headache | 42/104 | 2/8 | 40/96 | 0.584 |
| Palpitations | 42/104 | 2/8 | 40/96 | 0.584 |
| Sweating | 37/104 | 3/8 | 34/96 | 1.000 |
| Dizziness | 18/104 | 1/8 | 17/96 | 1.000 |
| Abdominal/back pain | 17/104 | 3/8 | 14/96 | 0.235 |
| Pallor | 10/104 | 0/8 | 10/96 | 1.000 |
| Nausea/vomiting | 11/104 | 1/8 | 10/96 | 1.000 |
| Fatigue | 7/104 | 2/8 | 5/96 | 0.090 |
| Hypertension | 80/104 | 7/8 | 73/96 | 0.762 |
| Classic triad, n/N | ||||
| 3 presented | 14/104 | 1/8 | 13/96 | 1.000 |
| 1－2 presented | 54/104 | 3/8 | 51/96 | 0.630 |
| None presented | 36/104 | 4/8 | 32/96 | 0.572 |
| BMI/(kg/m2) | 22.65(15.77-32.53) | 25.56(17.67-27.85) | 22.42(15.77-32.53) | 0.118 |
| Tumor diameter/cm | 5.00(1.20-14.00) | 4.75(1.20-6.00) | 5.00(1.50-14.00) | 0.081 |
分析此8例患者的就诊原因, 4例因头痛、心悸、多汗等典型PPGL临床症状就诊, 1例因腰痛, 1例因体检发现肾上腺意外瘤就诊, 2例为嗜铬细胞瘤术后复查就诊。对比MNs正常组和升高组患者的就诊原因, 差异无统计学意义(P=0.265)。
MNs正常组最常见的临床症状为多汗(3/8)、腰腹痛(3/8)、头痛(2/8)、心悸(2/8)和疲乏(2/8);其中具有典型三联征患者1例, 无任何三联征表现者4例; 此外, 7例患有高血压, 其中4例表现为阵发性高血压, 3例表现为持续性高血压, 且1例在持续性高血压基础上阵发性加重。对比MNs升高组, 各临床症状在两组间的发生率差异无统计学意义。MNs正常组患者入院时BMI平均为25.56(17.67~27.85) kg/m2, 有高于MNs升高组[22.42(15.77~32.53) kg/m2]的趋势, 但差异无统计学意义(P=0.118)。统计两组患者并发症情况, MNs正常组未见明显PPGL相关的靶器官损害, MNs升高组96例中可见8例出现儿茶酚胺心肌病, 6例合并高血压脑病(包括颅内出血3例、意识障碍2例、癫痫发作1例)。
对MNs正常PPGL患者的术前内分泌激素结果进行分析(表 4), 血浆游离型MN、NMN水平均显著低于MNs升高组(P均 < 0.05)。此外, 部分患者接受了血浆游离型3-MT、血儿茶酚胺及血CgA的检测。在MNs正常组中, 7例患者检测了血3-MT, 2例升高(患者5和6, 分别为2.27 nmol/L和0.23 nmol/L); 3例患者检测去甲肾上腺素, 2例升高(患者1和6, 分别为8.523 pmol/L和22.367 pmol/L), 无血肾上腺素或多巴胺升高者; 5例患者检测了血CgA, 2例升高(患者3和6, 分别为156.78 μg/L和1 295.36 μg/L)。与MNs升高组相比, 血3-MT和儿茶酚胺的诊断阳性率在组间差异无统计学意义, CgA诊断阳性率在MNs正常组较低, 差异有统计学意义(P=0.005)。
4.
MNs正常与MNs升高PPGL患者生化检测及影像学指标
Comparison of biochemical testing and imaging finding data between MNs normal and MNs elevated groups in PPGL patients
| MNs normal | MNs elevated | P value | |
| MNs, metanephrines; NMN, normetanephrine; PPGL, pheochromocytoma and paraganglioma; 3-MT, 3-methoxytyramine; E, epinephrine; NE, norepinephrine; DA, dopamine; CgA, chromogranin A. Reference interval: MN≤0.50 nmol/L, NMN≤0.90 nmol/L, 3-MT < 0.18 nmol/L; E 0.05-1.39 pmol/L, NE 0.51-3.26 pmol/L, DA 0.07-0.68 pmol/L; CgA 19.4-98.1 μg/L. | |||
| MN/(nmol/L) | 0.11(< 0.08-0.22) | 0.71(< 0.08->20.56) | |
| MN, n/N | 0/8 | 45/96 | 0.028 |
| NMN/(nmol/L) | 0.395(0.20-0.71) | 4.87(0.42->20.56) | |
| NMN, n/N | 0/8 | 94/96 | 0.000 |
| 3-MT/(nmol/L) | < 0.08(< 0.08-2.27) | 0.12(< 0.08-0.46) | |
| 3-MT, n/N | 2/7 | 6/93 | 0.096 |
| E/(pmol/L) | 0.049(0.027-0.169) | 0.087(0.027-89.138) | |
| E, n/N | 0/3 | 6/40 | 1.000 |
| NE/(pmol/L) | 8.523(0.467-22.367) | 9.836(0.284-147.23) | |
| NE, n/N | 2/3 | 31/40 | 0.558 |
| DA/(pmol/L) | 0.052(0.039-0.157) | 0.056(0.033-1.18) | |
| DA, n/N | 0/3 | 2/40 | 1.000 |
| CgA/(μg/L) | 60.02(34.37-1295.36) | 369.37(36.85-1669.96) | |
| CgA, n/N | 2/5 | 41/43 | 0.005 |
| Classic findings of CT, n/N | 5/8 | 85/96 | 0.125 |
104例患者均行增强CT检查, MNs正常组中6例为肾上腺占位, 2例为腹膜后占位; 7例为单发病变, 1例为单侧肾上腺占位合并肾转移(患者8)。有5例增强CT呈典型的不均匀强化, 其中1例奥曲肽显像阳性, 1例PET-CT阳性而MIBG阴性; 3例增强CT未见典型表现, 其中1例PET-CT阳性, 余患者未行功能影像学检查。对比两组患者CT典型表现的发生比例, 差异无统计学意义。
2.2. MNs正常PPGL患者的诊治方案、病理及随访情况
在8例MNs正常的PPGL患者术前诊断中, 2例因明确的PPGL既往史诊断为嗜铬细胞瘤复发, 2例因典型的症状和CT表现诊断为PPGL, 1例因血3-MT检测结果升高诊断为嗜铬细胞瘤, 1例因血CgA升高及PET-CT阳性诊断为嗜铬细胞瘤。此外, 术前诊断为无功能腺瘤者、原发性醛固酮增多症者各1例。8名患者均应用α受体阻滞剂行术前准备10~60 d不等, 其中6例行腹腔镜手术, 2例行开腹手术, 除1例开腹患者术中平均动脉压 < 60 mmHg, 余患者术中均未见血压波动(表 2)。
分析患者术后组织病理学诊断, MNs正常组中嗜铬细胞瘤6例, 副神经节瘤2例。对比MNs升高组, 肿瘤发生部位在组间差异无统计学意义。MNs正常组肿瘤直径略小于MNs升高组, 但差异无统计学意义[4.75(1.20~6.00) cm vs. 5.00(1.50~14.00) cm, P=0.081]。MNs正常组的组织病理学结果显示, 2例标本有细胞异形性, 3例可见大量组织坏死, 其中1例肿瘤组织仅见少量瘤细胞残存, 该例患者肿瘤组织Ki67>20%, 余肿瘤Ki67均 < 5%。
8例MNs正常患者术后随访中位随访时间为1.5(0.5-4.5)年。3例行血MNs、3-MT或CgA检查, 其中2例(患者1和6)上述指标术前有升高, 且均于术后恢复正常; 1例(患者7)手术前后3-MT、CgA均为正常。MNs正常组全部复查影像学检查, 均未见复发或转移征象。
3. 讨论
血浆游离型MNs相较于其他儿茶酚胺激素及其代谢产物, 可显著提高PPGL的诊断敏感性、降低假阴性[7]。MNs正常的PPGL较为少见, 截至目前, 仅见少量病例报道和回顾性研究[9-10, 12-15]。本研究散发性PPGL患者血MNs正常的比例为7.69%, 与Heavner等[15]的研究结果相近(7/78, 9%), 略低于曹万里等[10]的报道(24/189, 12.7%)。曹万里等[10]的研究应用了高效液相色谱电化学法进行血浆游离型MNs的检测, 而Heavner等[15]的研究针对不同病例分别采用了血、尿MNs及儿茶酚胺等检测, 因此可见检测方法及诊断标准的不同或对检测结果造成一定影响。
本研究比较MNs正常和升高组PPGL患者的临床特点, 两组患者的临床症状未见明显差异, 因此, 对于具有典型症状的肾上腺或腹膜后占位患者, 即便其MNs正常, 仍需警惕PPGL的可能。另外, 本研究8例MNs正常组患者的BMI有高于升高组的趋势, 与Heavner等[15]和曹万里等[10]的研究结果相似。Heavner等[15]认为, BMI偏高患者的血容量相对较多, 可能对循环血MNs浓度造成稀释, 从而导致其假性正常; 曹万里等[10]则推测较高的儿茶酚胺水平可致患者体重下降。本研究的8例MNs正常患者中, 2例患者血NE水平升高2.6~6.9倍, 而MNs升高组患者的平均NE水平为正常者的3倍, 最高者可至45倍, 因此认为MNs正常组肿瘤的儿茶酚胺合成、代谢水平可能较低, 患者代谢消耗偏低, 因而BMI可能偏高; 而MNs升高组患者的心脑血管并发症明显高于MNs正常组, 亦可能与儿茶酚胺水平差异有关。
血MNs检测正常的原因可能包括:(1)肿瘤体积较小:PPGL肿瘤大小与血、尿MNs表达水平存在正相关性, 因此肿瘤体积 < 1 cm时可能出现MNs正常的情况[16]。本研究8例MNs正常患者中3例的肿瘤直径≤1.5 cm(患者1、2和4), 而MNs升高组96例中肿瘤直径≤1.5 cm者仅1例, 支持了这一观点。(2)肿瘤大量坏死:本研究8例MNs正常患者中3例的病理组织提示肿瘤大量坏死(患者5、7和8), 推测因为肿瘤细胞大量坏死, 破坏了其儿茶酚胺激素分泌、合成及代谢功能, 导致MNs检测正常。(3)检测方法所致假阴性:MNs的检测可应用LC-MS、液相色谱电化学法(liquid chromatography with electrochemical or fluorometric detection, LC-ECD)、放射免疫法或酶联免疫法等方法[6], 不同检测方法的敏感性、特异性有所区别, 既往研究显示, 相较于免疫法而言, LC-MS和LC-ECD更为精准[17-18]。本研究应用了MNs诊断敏感性最高的LC-MS检测法, 与中国专家共识和美国指南的首选推荐一致。
本研究回顾了其他生化检验及影像学检查对MNs正常者PPGL诊断的贡献, 结果表明, 血3-MT可对MNs正常PPGL的诊断起到一定帮助, CgA的诊断效能在MNs正常组相对偏低。既往文献显示[5], CgA的特异性相对较低, 因此并不推荐其作为PPGL确诊的首选检验方法。但对于MNs正常患者, CgA升高仍有一定的诊断意义, 这与欧洲内分泌协会对于MNs正常PPGL的术前筛查推荐方案一致[8]。虽然血MNs的诊断效能显著高于血儿茶酚胺, 但本研究显示, 2例MNs正常患者的血NE水平升高(患者1、6), 因此血MNs和血儿茶酚胺的检测存在互补性。在影像学方面, 本研究发现增强CT典型表现的发生率在MNs正常组和升高组间差异并无统计学意义, 提示影像学检查有助于MNs正常者PPGL的诊断。此外, 本研究2例患者PET-CT检查阳性、1例奥曲肽显像阳性, 均对MNs正常组PPGL诊断有一定的帮助。因此, 结合患者症状、辅助检查结果的综合诊断至关重要。
回顾MNs正常患者的诊治方案, 本研究8例患者均于术前行α受体阻滞剂准备, 其中1例(患者7)存在术中平均动脉压过低。美国内分泌协会推荐, 对于所有有功能的PPGL均应术前应用α受体阻滞剂[6], 而中华医学会内分泌学分会指出, 不推荐头颈部及分泌DA的PPGL进行术前药物准备[7]。目前对于MNs正常者PPGL的术前用药尚无明确建议。Kota等[14]对未行术前准备的血、尿MNs正常者PPGL行肿瘤切除时, 患者术中血压出现显著波动。因此, 对于MNs正常PPGL患者, 仍需术前使用α受体阻滞剂, 但应避免药物过量导致术中发生低血压。
此外, 本研究MNs正常组中有PPGL复发患者2例(患者1和8), 其中患者8合并转移, 患者1此次复发距初发时间间隔8年, 且初发时患者血NE水平显著升高, 由此可见, MNs升高患者如术后出现新发肿瘤事件, 即使检测血MNs水平正常, 仍需警惕PPGL复发, 而患者8多次血、尿MNs和MIBG检查均为阴性, 后因PET-CT阳性确诊复发合并转移, 提示对于MNs正常患者术后应保持规律随访, 并注重功能影像学检查。
对于随访, 本研究结果显示2例其他生物标志物升高的患者术后随访均恢复正常, 说明MNs正常患者术后应规律监测术前升高的生物标志物的变化, 这有助于判断手术治疗效果、监测有无复发, 与欧洲内分泌协会的随访推荐方案一致[8]。
本研究为回顾性研究, 因此可能存在选择性偏倚, 此外, 本研究收集的MNs正常的PPGL患者例数较少, 对检验效能产生一定影响, 因此, 上述结果仍需扩大样本量进一步证实。
综上所述, MNs正常的PPGL在临床上相对少见, 对有典型临床表现的患者, 不应根据MNs结果正常轻易除外PPGL, 尤其当患者肿瘤体积相对较小或存在大量坏死时, 对于该类患者, 行血儿茶酚胺、3-MT、CgA等生化指标检查有助于明确诊断。增强CT的典型表现及PET-CT、奥曲肽等功能影像学检查均可对诊断提供一定帮助。MNs正常患者术前仍应使用α受体阻滞剂, 但需避免药物过量导致术中低血压发生。对已知PPGL病史的患者, 如出现新发肿瘤, 即使MNs检测正常, 仍应高度警惕PPGL复发、转移的可能。对MNs正常的PPGL患者, 推荐术后监测术前检测升高指标(如3-MT、CgA、儿茶酚胺等)及定期监测影像学改变。
Funding Statement
北京大学临床研究项目(PUCRP201302)、北京大学医学交叉研究种子基金(BMU2018MX026)和北京大学第一医院科研种子基金(2018SF066)
Supported by PUHSC Clinical Research Project(PUCRP201302), Interdisciplinary Medicine Seed Fund of Peking University(BMU2018MX026), and the Scientific Research Seed Fund of Peking University First Hospital (2018SF066)
Contributor Information
高 莹 (Ying GAO), Email: bjgaoying@yahoo.com.
张 争 (Zheng ZHANG), Email: doczhz@aliyun.com.
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