Diagnosis, Pathophysiology And Molecular Biology of Pheochromocytoma and Paraganglioma

嗜铬细胞瘤和副神经节瘤的诊断、病理生理学和分子生物学

• 批准号: 10685192
• 负责人: Karel Pacak
• 金额: $ 233.26万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685192
• 关键词: Adrenal Gland Neoplasms; Adrenergic Receptor; Age; Agreement; Anti-CD40; Antibodies; Basic Science; Bilateral; Biochemical; Biological Markers; Bladder Paraganglioma; CD4 Positive T Lymphocytes; Carotid Body; Catecholamines; Cells; Chemistry; Clinical; Clinical Trials; Collaborations; Comparative Study; Consensus; Cystectomy; Data; Development; Diagnosis; Diagnostic; Disseminated Malignant Neoplasm; Distal; Distant; Dopamine; Endocrinologist; Enzymes; Epidemiology; Etiology; Evaluation; Event; Excision; Flow Cytometry; Functional disorder; Future; Genes; Genetic; Germ-Line Mutation; Goals; Growth; Guidelines; Head and Neck Paraganglioma; Health Professional; Hematuria; Hypertension; Image; Image Analysis; Immune; Immunologic Markers; Immunologic Memory; Immunotherapy; Infiltration; Injections; Institutes; Institution; Interdisciplinary Study; International; Intraoperative Complications; Knowledge; Laboratories; Lesion; Ligands; Link; Liver; Location; Magnetic Resonance Imaging; Mannans; Measurement; Medical; Medical Genetics; Medical center; Metastatic Pheochromocytoma; Methods; MicroRNAs; Modality; Modeling; Molecular; Molecular Biology; Molecular Genetics; Monitor; Multicenter Studies; Mus; Mutation; Neoplasm Metastasis; Neuroendocrine Tumors; Neuroendocrinology; Operative Surgical Procedures; Outcome; PET/CT scan; Paraganglioma; Pathogenesis; Pathway interactions; Patients; Pheochromocytoma; Plasma; Primary Neoplasm; Production; Professional Organizations; Reporting; Research Personnel; Residual Tumors; Resistance; Secondary to; Sex Differences; Solid; Spleen; Succinate Dehydrogenase; Surgical Management; Technology; Testing; Therapeutic Intervention; Tracer; Translational Research; Transurethral Resection; United States National Institutes of Health; Visualization; Woman; analytical method; anti-tumor immune response; associated symptom; base; cancer therapy; clinical application; clinical diagnosis; driving force; fluorodeoxyglucose positron emission tomography; genetic disorder diagnosis; imaging modality; improved; meetings; men; metabolomics; mutation carrier; patient oriented; patient oriented research; recruit; subcutaneous; symposium; tumor; tumor diagnosis; tumorigenesis

The Section is conducting patient-oriented research about the etiology, epidemiology, pathophysiology, genetics, diagnosis, and treatment of pheochromocytoma and paraganglioma (PPGL). Projects include not only translational research-applying basic science knowledge to clinical diagnosis, pathophysiology, and treatment-but also reverse translation research where appreciation of clinical findings leads to new concepts that basic researchers can pursue in the laboratory. In order to achieve our goals, the strategy of the Section is based on the multidisciplinary collaborations among NIH investigators and outside medical centers/institutions. Our Section links together a patient-oriented component with two bench-level components. The patient-oriented component (Medical Neuroendocrinology) is currently the main driving force for our hypotheses and discoveries. The two bench-level components (Tumor Pathogenesis, Genetics, Chemistry & Biomarkers and Experimental Immunotherapies) emphasize first, technologies of basic research tailored for pathway and target discovery and second, the development of the discoveries into clinical applications. Clinical and genetic aspects of PPGLs Head and neck paragangliomas (HNPGLs) are tumors of parasympathetic origin that occur at variable locations and are often secondary to germline mutations in succinate dehydrogenase (SDH) subunit genes. We assessed whether different locations of HNPGLs relate to the presence of SDHx mutations, catecholamine production and other presentations. In this multicenter study, we collected clinical and biochemical data from 244 patients with HNPGLs and 71 patients without HNPGLs. We clarified that jugulotympanic HNPGLs have distinct features. In particular, 88% of jugulotympanic HNPGLs arose in women, among whom only 24% occurred due to SDHx mutations compared to 55% in men. Jugulotympanic HNPGLs were also rarely bilateral, were of a smaller size and were less often metastatic compared to carotid body and vagal HNPGLs. Furthermore, we showed that plasma concentrations of methoxytyramine (MTY) were higher (P < 0.0001) in patients with HNPGL than without HNPGL, whereas plasma normetanephrine did not differ. Only 3.7% of patients showed strong increases in plasma normetanephrine. Plasma MTY was positively related to tumor size but did not relate to the presence of SDHx mutations or tumor location. Our findings confirm that increases in plasma MTY represent the main catecholamine-related biochemical feature of patients with HNPGLs. We expect that more sensitive analytical methods will make biochemical testing of HNPGLs more practical in the future and enable more than the current 30% of patients to be identified with dopamine-producing HNPGLs. The sex-dependent differences in the development of HNPGLs may have relevance to the diagnosis, management and outcomes of these tumors. Paraganglioma of the urinary bladder (UBPGL) is a rare neuroendocrine tumor diagnosed in many patients only after surgery. We, therefore, assessed clinical clues relevant to presurgical diagnosis and clinical consequences in patients with a missed presurgical diagnosis of UBPGL based on international collaboration. We included 177 articles reporting 194 cases. In 90 (46.4%) patients, the UBPGL was diagnosed before and in 104 (53.6%) after surgery. In presurgically diagnosed UBPGL, hypertension and catecholamine-associated symptoms were 2- to 3-fold (p < 0.001) more frequent than in postsurgically diagnosed patients whereas hematuria was twofold (p = 0.003) more prevalent in those with postsurgical diagnosis. Hypertension was an independent factor for presurgical biochemical testing (OR 4.45, 95% CI 1.66-11.94) while hematuria (OR 0.23, 95% CI 0.09-0.60) was an independent factor for not performing presurgical biochemical testing. Most patients diagnosed after surgery were not pretreated with alpha-adrenoceptor blockade (95.2%), underwent more frequently transurethral resection instead of cystectomy (70.2% vs. 23.1%) and had more frequent peroperative complications and residual tumor mass. We concluded that in nearly half of all patients with a UBPGL, the diagnosis was not established before surgery. Hypertension and hematuria contributed independently to a presurgical diagnosis. Postsurgical diagnosis, which was associated with suboptimal presurgical and surgical management, resulted in more peroperative complications and incomplete tumor resections. We also identified candidate miRNA and lncRNAs associated with metastasis-free survival in PCPGs (e.g. USP3-AS1, LINC00877, and AC009312.1). Imaging aspects of PPGLs The purpose of this study was to perform an intraindividual comparison of 68Ga-DOTATATE PET/CT, FDG PET/CT, 18F-FDOPA PET/CT, 18F-FDA PET/CT, CT, and MRI in visualization of sporadic primary PHEO. The analysis included 14 patients (eight women, six men; mean age, 52.4 16.8 SD years) with PHEO. Both 68Ga-DOTATATE PET/CT and FDG PET/CT were completed in all 14 patients, 18F-FDOPA PET/CT in 11, 18F-FDA PET/CT in 7, CT in 12, and MRI in 12. Mean conspicuity score for PHEO was 5.0 0.0 for 18F-FDOPA PET/CT, 4.7 0.5 for MRI, 4.6 0.8 for 18F-FDA PET/CT, 4.4 1.0 for 68Ga-DOTATATE PET/CT, 4.3 1.0 for CT, and 4.1 1.5 for FDG PET/CT. The positivity rate for PHEO was 100.0% (11/11) for 18F-FDOPA PET/CT, 100.0% (12/12) for MRI, 85.7% (6/7) for 18F-FDA PET/CT, 78.6% (11/14) for FDG PET/CT, 78.6% (11/14) for 68Ga-DOTATATE PET/CT, and 66.7% (8/12) for CT. Lesion-to-liver SUVmax was 10.5 for 18F-FDOPA versus 3.0-4.2 for the other tracers. Interreader agreement across modalities ranged from 85.7% to 100.0% for lesion positivity with ICCs of 0.55-1.00 for SUVmax measurements. CONCLUSION. Findings from this small intraindividual comparative study support 18F-FDOPA PET/CT as a preferred first-line imaging modality in evaluation of sporadic PHEO. CLINICAL IMPACT. This study provides data supporting current guidelines for imaging evaluation of suspected PHEO. Immune aspects of PPGLs Immunotherapy has become an essential component in cancer treatment. However, the majority of solid metastatic cancers, such as pheochromocytoma, are resistant to this approach. Therefore, understanding immune cell composition in primary and distant metastatic tumors is important for therapeutic intervention and diagnostics. Combined mannan-BAM, TLR ligand, and anti-CD40 antibody-based intratumoral immunotherapy (MBTA therapy) previously resulted in the complete eradication of murine subcutaneous pheochromocytoma and demonstrated a systemic antitumor immune response in a metastatic model. Here, we further evaluated this systemic effect using a bilateral pheochromocytoma model, performing MBTA therapy through injection into the primary tumor and using distant (non-injected) tumors to monitor size changes and detailed immune cell infiltration. MBTA therapy suppressed the growth of not only injected but also distal tumors and prolonged MBTA-treated mice survival. Our flow cytometry analysis showed that MBTA therapy led to increased recruitment of innate and adaptive immune cells in both tumors and the spleen. Moreover, adoptive CD4+ T cell transfer from successfully MBTA-treated mice (i.e., subcutaneous pheochromocytoma) demonstrates the importance of these cells in long-term immunological memory. In summary, this study unraveled further details on the systemic effect of MBTA therapy and its use for tumor and metastasis reduction or even elimination. PPGL guidelines/consensus Approximately 20% of patients diagnosed with PPGLs carry a mutation in one of the succinate dehydrogenase genes (SDHA, SDHB, SDHC and SDHD), which encode the four subunits of the SDH enzyme. This International Consensus Statement focused on the management of asymptomatic SDHx mutation carriers and provides clinicians with much-needed clinical guidan

该科正在以患者为中心开展有关嗜铬细胞瘤和副神经节瘤（PPGL）的病因学、流行病学、病理生理学、遗传学、诊断和治疗的研究。项目不仅包括转化研究——将基础科学知识应用于临床诊断、病理生理学和治疗——还包括逆向转化研究，其中对临床发现的理解导致基础研究人员可以在实验室中追求的新概念。 为了实现我们的目标，该科的战略基于 NIH 研究人员和外部医疗中心/机构之间的多学科合作。我们的部分将面向患者的组件与两个工作台级组件连接在一起。以患者为导向的部分（医学神经内分泌学）目前是我们的假设和发现的主要驱动力。两个实验室级组成部分（肿瘤发病机制、遗传学、化学和生物标志物以及实验免疫疗法）首先强调为途径和靶标发现量身定制的基础研究技术，其次强调将发现发展到临床应用。 PPGL 的临床和遗传方面 头颈副神经节瘤 (HNPGL) 是副交感神经起源的肿瘤，发生在不同部位，通常继发于琥珀酸脱氢酶 (SDH) 亚基基因的种系突变。我们评估了 HNPGL 的不同位置是否与 SDHx 突变的存在、儿茶酚胺的产生和其他表现有关。在这项多中心研究中，我们收集了 244 名患有 HNPGL 的患者和 71 名不患有 HNPGL 的患者的临床和生化数据。我们阐明颈鼓室 HNPGL 具有独特的特征。特别是，88% 的颈鼓室 HNPGL 发生在女性中，其中只有 24% 是由于 SDHx 突变而发生，而男性中这一比例为 55%。与颈动脉体和迷走神经 HNPGL 相比，颈鼓室 HNPGL 也很少是双侧的，尺寸较小，且不易发生转移。此外，我们发现，HNPGL 患者的血浆甲氧基酪胺 (MTY) 浓度高于未患 HNPGL 的患者 (P < 0.0001)，而血浆去甲肾上腺素没有差异。仅 3.7% 的患者血浆去甲肾上腺素显着升高。血浆 MTY 与肿瘤大小呈正相关，但与 SDHx 突变的存在或肿瘤位置无关。我们的研究结果证实，血浆 MTY 的增加代表了 HNPGL 患者与儿茶酚胺相关的主要生化特征。我们预计，更灵敏的分析方法将使 HNPGL 的生化检测在未来更加实用，并使目前超过 30% 的患者能够被鉴定出产生多巴胺的 HNPGL。 HNPGL 发育的性别依赖性差异可能与这些肿瘤的诊断、治疗和结果相关。 膀胱副神经节瘤（UBPGL）是一种罕见的神经内分泌肿瘤，许多患者仅在手术后才被诊断出来。因此，我们基于国际合作，评估了与 UBPGL 术前漏诊患者的术前诊断相关的临床线索和临床后果。我们收录了 177 篇文章，报告了 194 个案例。 90 例 (46.4%) 患者在手术前和 104 例 (53.6%) 术后被诊断为 UBPGL。在术前诊断的 UBPGL 中，高血压和儿茶酚胺相关症状的发生率是术后诊断患者的 2 至 3 倍 (p < 0.001)，而血尿在术后诊断的患者中发生率是其两倍 (p = 0.003)。高血压是术前生化检测的独立因素（OR 4.45，95% CI 1.66-11.94），而血尿（OR 0.23，95% CI 0.09-0.60）是不进行术前生化检测的独立因素。大多数术后诊断的患者未接受α-肾上腺素受体阻滞剂预处理（95.2%），更频繁地接受经尿道切除术而不是膀胱切除术（70.2% vs. 23.1%），并且围手术期并发症和残留肿瘤块更频繁。我们得出的结论是，近一半的 UBPGL 患者在手术前并未确诊。高血压和血尿独立影响术前诊断。术后诊断与术前和手术管理欠佳相关，导致更多的围手术期并发症和肿瘤切除不完全。 我们还鉴定了与 PCPG 中无转移生存相关的候选 miRNA 和 lncRNA（例如 USP3-AS1、LINC00877 和 AC009312.1）。 PPGL 的成像方面 本研究的目的是对 68Ga-DOTATATE PET/CT、FDG PET/CT、18F-FDOPA PET/CT、18F-FDA PET/CT、CT 和 MRI 在散发性原发性 PHEO 可视化方面进行个体间比较。该分析包括 14 名 PHEO 患者（8 名女性，6 名男性；平均年龄，52.4±16.8 SD 岁）。所有 14 名患者均完成了 68Ga-DOTATATE PET/CT 和 FDG PET/CT，11 名患者完成了 18F-FDOPA PET/CT，7 名患者完成了 18F-FDA PET/CT，12 名患者完成了 CT，12 名患者完成了 MRI。 PHEO 的平均显着性评分为 5.0 0.0，18F-FDOPA PET/CT 为 4.7 MRI 0.5，18F-FDA PET/CT 4.6 0.8，4.4 1.0 对于 68Ga-DOTATATE PET/CT，对于 CT 为 4.3 1.0，对于 FDG PET/CT 为 4.1 1.5。 PHEO阳性率：18F-FDOPA PET/CT为100.0%（11/11），MRI为100.0%（12/12），18F-FDA PET/CT为85.7%（6/7），FDG PET/CT为78.6%（11/14），FDG PET/CT为78.6%（11/14）。 68Ga-DOTATATE PET/CT，66.7% (8/12) 进行 CT 检查。 18F-FDOPA 的病变至肝脏 SUVmax 为 10.5，而其他示踪剂为 3.0-4.2。对于病变阳性，跨模式的读者间一致性范围为 85.7% 至 100.0%，SUVmax 测量的 ICC 为 0.55-1.00。结论。这项小型个体内比较研究的结果支持 18F-FDOPA PET/CT 作为评估散发性 PHEO 的首选一线成像方式。临床影响。这项研究提供了支持当前疑似 PHEO 影像学评估指南的数据。 PPGL 的免疫方面 免疫疗法已成为癌症治疗的重要组成部分。然而，大多数实体转移癌，例如嗜铬细胞瘤，对这种方法有抵抗力。因此，了解原发性和远处转移性肿瘤中的免疫细胞组成对于治疗干预和诊断非常重要。联合甘露聚糖-BAM、TLR配体和基于抗CD40抗体的瘤内免疫疗法（MBTA疗法）先前导致完全根除小鼠皮下嗜铬细胞瘤，并在转移模型中证明了全身抗肿瘤免疫反应。在这里，我们使用双侧嗜铬细胞瘤模型进一步评估了这种全身效应，通过注射到原发性肿瘤中进行MBTA治疗，并使用远处（未注射）的肿瘤来监测大小变化和详细的免疫细胞浸润。 MBTA 疗法不仅抑制了注射肿瘤的生长，还抑制了远端肿瘤的生长，并延长了 MBTA 治疗小鼠的生存期。我们的流式细胞术分析表明，MBTA 疗法导致肿瘤和脾脏中先天性和适应性免疫细胞的募集增加。此外，成功MBTA治疗小鼠（即皮下嗜铬细胞瘤）的过继CD4+ T细胞转移证明了这些细胞在长期免疫记忆中的重要性。总之，这项研究进一步揭示了 MBTA 疗法的全身效应及其在减少甚至消除肿瘤和转移方面的用途。 PPGL 指南/共识 大约 20% 被诊断为 PPGL 的患者携带琥珀酸脱氢酶基因之一（SDHA、SDHB、SDHC 和 SDHD）突变，该基因编码 SDH 酶的四个亚基。该国际共识声明重点关注无症状 SDHx 突变携带者的管理，为临床医生提供急需的临床指导