生化阴性的嗜铬细胞瘤/副神经节瘤患者的临床特征及术中血流动力学不稳定的危险因素

Clinical characteristics of patients with biochemically negative pheochromocytoma/paraganglioma and risk factors for intraoperative hemodynamics instability

摘要

目的 分析生化阴性的嗜铬细胞瘤/副神经节瘤（PPGL）患者的临床特征，并探讨其术中血流动力学不稳定（IHI）的危险因素，为临床诊断及围手术期管理提出建议。方法 回顾性分析2016年12月至2023年11月在河南省人民医院接受手术并经病理确诊的181例PPGL患者的临床资料。根据血浆游离甲氧基肾上腺素（MN）与甲氧基去甲肾上腺素（NMN）水平，将患者分为生化阴性组（n = 52）和生化阳性组（n = 129）。比较两组患者在临床表现、实验室检查、影像学特征、术前准备及术中血流动力学变化等方面的差异；进一步对生化阴性组患者中IHI与非IHI亚组进行单因素logistic回归分析，以确定IHI的相关因素。结果 生化阴性组患者的体重、病程及休克发生率高于生化阳性组，而糖尿病患病率、收缩压和心率低于生化阳性组（均P＜0.05）。生化阴性组患者血钙、血浆肾素活性及皮质醇水平均显著低于生化阳性组，而醛固酮/肾素比值则显著升高（均P＜0.05）。影像学显示，生化阴性组功能影像学阳性率低于阳性组（63.6%比100%，P = 0.008），肿瘤最大直径亦显著较小。尽管IHI总体发生率在生化阴性组较低（23.4%比42.1%，χ² = 4.778，P = 0.029），但仍有部分患者发生显著血流动力学波动。单因素logistic回归分析显示，空腹血糖（OR = 1.961，95%CI：1.128～3.410）、空腹血糖升高（OR = 6.125，95%CI：1.425～26.328）及肿瘤直径＞4 cm（OR = 7.071，95%CI：1.328～37.651）与IHI发生相关。结论 生化阴性PPGL具有相对隐匿的临床与影像学特征。该类患者术中仍存在IHI风险。肿瘤直径＞4 cm、空腹血糖升高与IHI发生相关，围手术期应加强风险评估与管理。

Abstract

Objective To investigate the clinical characteristics of biochemically negative pheochromocytoma and paraganglioma (PPGL) and to identify risk factors associated with intraoperative hemodynamics instability (IHI), providing guidance for diagnosis and perioperative management. Methods A retrospective analysis was conducted on 181 PPGL patients who underwent surgical resection and were pathologically confirmed at Henan University People’s Hospital between December 2016 and November 2023. Patients were divided into a biochemically negative group (n = 52) and a biochemically positive group (n = 129) based on plasma free metanephrine (MN) and normetanephrine (NMN) levels. Clinical features, laboratory data, imaging findings, preoperative preparation, and intraoperative hemodynamic changes were compared between groups. Logistic regression analysis was performed to identify risk factors for IHI among the biochemically negative subgroup. Results The weight, duration of onset and incidence of shock in the biochemical negative group were higher than those in the biochemical positive group, while the prevalence of diabetes, systolic blood pressure and heart rate were lower than those in the biochemical positive group (all P＜0.05). Biochemically negative patients exhibited lower serum calcium, renin activity, and cortisol levels, whereas the aldosterone-to-renin ratio was higher (all P＜ 0.05). Functional imaging positivity was significantly lower in the negative group (63.6% vs 100%, P = 0.008), and the maximal tumor diameter was smaller. Although the overall incidence of IHI was low in the biochemical negative group (23.4% vs 42.1%, χ² = 4.778, P = 0.029), there were still some patients with significant hemodynamic fluctuations. Univariate logistic regression analysis showed that fasting glucose (OR = 1.961, 95%CI: 1.128 to 3.410), elevated fasting glucose (OR = 6.125, 95%CI: 1.425 to 26.328), and tumor diameter ＞4 cm (OR = 7.071, 95%CI: 1.328 to 37.651) were significantly associated with IHI. Conclusions Biochemically negative PPGL presents with relatively subtle clinical and imaging features. These patients remain at risk for IHI. Tumor diameter ＞4 cm, elevated fasting blood glucose were associated with IHI. Therefore, enhanced risk assessment and management should be implemented during the perioperative period.

关键词

嗜铬细胞瘤 / 副神经节瘤 / 生化阴性 / 甲氧基肾上腺素 / 术中血流动力学不稳定

Key words

pheochromocytoma / paraganglioma / biochemically negative / metanephrine / intraoperative hemodynamics instability

参考文献

[1] Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline[J]. J Clin Endocrinol Metab, 2014, 99(6): 1915-1942.

[2] Lam AK . Update on Adrenal Tumours in 2017 World Health Organization (WHO) of endocrine tumours[J]. Endocr Pathol, 2017, 28(3): 213-227.

[3] Berends AMA, Buitenwerf E, de Krijger RR, et al. Incidence of pheochromocytoma and sympathetic paraganglioma in the netherlands: a nationwide study and systematic review[J]. Eur J Intern Med, 2018, 51: 68-73.

[4] Calissendorff J, Juhlin CC, Bancos I, et al. Pheochromocytomas and abdominal paragangliomas: a practical guidance[J]. Cancers (Basel), 2022, 14(4): 917.

[5] Kaplinsky A, Halperin R, Shlomai G, et al. Role of epigenetic regulation on catecholamine synthesis in pheochromocytoma and paraganglioma[J]. Cancer, 2024, 130(19): 3289-3296.

[6] Eisenhofer G, Pamporaki C, Lenders JWM . Biochemical assessment of pheochromocytoma and paraganglioma[J]. Endocr Rev, 2023, 44(5): 862-909.

[7] Chen Y, Xiao H, Zhou X, et al. Accuracy of plasma free metanephrines in the diagnosis of pheochromocytoma and paraganglioma: a systematic review and meta—analysis[J]. Endocr Pract, 2017, 23(10): 1169-1177.

[8] Constantinescu G, Preda C, Constantinescu V, et al. Silent pheochromocytoma and paraganglioma: systematic review and proposed definitions for standardized terminology[J]. Front Endocrinol (Lausanne), 2022, 13: 1021420.

[9] Zhao L, Zhang X, Meng X, et al. The clinical characteristics of pheochromocytomas and paragangliomas with negative catecholamines[J]. J Clin Med, 2022, 11(19): 5583.

[10] 刘鹭, 田杰, 吴恺, 等 . 血浆游离型甲氧基肾上腺素类物质检测正常的嗜铬细胞瘤和副神经节瘤的临床特点[J]. 北京大学学报(医学版), 2020, 52(4): 614-620.

[11] 中华医学会糖尿病学分会 . 中国糖尿病防治指南(2024版)[J]. 中华糖尿病杂志, 2025, 17(1): 16-139.

[12] Mete O, Asa SL, Giil AJ, et al. Overview of the 2022 WHO classification of paragangliomas and pheochromocytomas[J]. Endocr Pathol, 2022, 33(1): 90-114.

[13] Juhlin CC, Mete O . Advances in adrenal and extra—adrenal paraganglioma: practical synopsis for pathologists[J]. Adv Anat Pathol, 2023, 30(1): 47-57.

[14] Carrasquillo JA, Chen CC, Jha A, et al. Imaging of pheochromocytoma and paraganglioma[J]. J Nucl Med, 2021, 62(8): 1033-1042.

[15] Taïeb D, Hicks RJ, Hindié E, et al. European Association of Nuclear Medicine Practice Guideline/Society of Nuclear Medicine and Molecular Imaging Procedure Standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma[J]. Eur J Nucl Med Mol Imaging, 2019, 46(10): 2112-2137.

[16] Kim JH, Lee HC, Kim SJ, et al. Perioperative hemodynamics instability in pheochromocytoma and sympathetic paraganglioma patients[J]. Sci Rep, 2021, 11(1): 18574.

[17] 《嗜铬细胞瘤围术期管理专家共识》专家编写组 . 嗜铬细胞瘤围术期管理专家共识(2025版)[J]. 中华内分泌外科杂志(中英文), 2025, 19(6): 793-800.

[18] Timmers HJ, Pacak K, Huynh TT, et al. Biochemically silent abdominal paragangliomas in patients with mutations in the succinate dehydrogenase subunit B gene[J]. J Clin Endocrinol Metab, 2008, 93(12): 4826-4832.

[19] Nölting S, Bechmann N, Taïeb D, et al. Personalized management of pheochromocytoma and paraganglioma[J]. Endocr Rev, 2022, 43(2): 199-239.

[20] Rezkallah E, Elsaify A, Hanna R, et al. Correlation between the size of pheochromocytoma and the level of metanephrines[J]. Endocr Regul, 2023, 57(1): 183-190.

[21] Eugster PJ, Maurer J, Vocat C, et al. Proneuropeptide Y and neuropeptide Y metabolites in healthy volunteers and patients with a pheochromocytoma or paraganglioma[J]. Clin Chim Acta, 2022, 534: 146-155.

[22] Ruike Y, Suzuki S, Yokote K . Increasing catecholamine secretion through NPY in pheochromocytomas with false—negative¹²³I—MIBG scintigraphy [J]. Clin Nucl Med, 2024, 49(5): 419-426.

[23] Smith SL, Slappy AL, Fox TP, et al. Pheochromocytoma producing vasoactive intestinal peptide[J]. Mayo Clin Proc, 2002, 77(1): 97-100.

[24] Eurin J, Barthélemy C, Masson F, et al. Release of neuropeptide Y and hemodynamic changes during surgical removal of human pheochromocytomas[J]. Regulatory Peptides, 2000, 86(1): 95-102.

[25] Gardiner SM, Kemp PA, March JE, et al. Regional haemodynamic effects of human and rat adrenomedullin in conscious rats[J]. Br J Pharmacol, 1995, 114(3): 584-591.

[26] Geven C, Bergmann A, Kox M, et al. Vascular effects of adrenomedullin and the anti—adrenomedullin antibody adrecizumab in sepsis[J]. Shock, 2018, 50(2): 132-140.

[27] Bruynzeel H, Feelders RA, Groenland TH, et al. Risk factors for hemodynamics instability during surgery for pheochromocytoma[J]. J Clin Endocrinol Metab, 2010, 95(2): 678-685.

[28] Lopez C, Bima C, Bollati M, et al. Pathophysiology and management of glycemic alterations before and after surgery for pheochromocytoma and paraganglioma[J]. Int J Mol Sci, 2023, 24(6): 5153.

[29] Groeben H, Nottebaum BJ, Alesina PF, et al. Perioperative alpha—receptor blockade in phaeochromocytoma surgery: an observational case series[J]. Br J Anaesth, 2017, 118(2): 182-189.

基金资助

国家自然科学基金(82270463)

河南省医学科技攻关计划省部共建重点项目(SBGJ202402004)

河南省科学技术厅重点研发专项(251111312800)

河南省临床研究型医生培养专项(HNCRD202402)