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: 10455959
• 负责人: Karel Pacak
• 金额: $ 271.35万
• 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/10455959
• 关键词: 13 year old; 16 year old; Abdomen; Adrenal Gland Neoplasms; Adrenal Glands; Affect; Age; Algorithms; Allografting; Animal Model; Apoptosis; Architecture; Artificial Intelligence; Ascorbic Acid; Basic Science; Biological Markers; CDX2 gene; Carrier Proteins; Catecholamines; Cauda Equina; Cell membrane; Cells; Chemistry; Chest; Child; Clinical; Clinical Trials; Collaborations; Companions; Consensus; Data; Data Analyses; Development; Diagnosis; Diagnostic; Diagnostic Specificity; Dimensions; Duodenum; Emerging Technologies; Endocrinologist; Epidemiology; Epithelial; Epithelioid Cells; Etiology; European; Evaluation; Event; Female; Fumarates; Functional Imaging; Functional disorder; GATA3 gene; Ganglia; Genetic; Genotype; Glial Fibrillary Acidic Protein; Glutathione; Goals; Guidelines; Head and neck structure; Health Professional; Homeostasis; Hypertension; Image; Immunohistochemistry; Immunologic Markers; Immunotherapy; Institutes; Institution; Interdisciplinary Study; International; Iron; Iron Overload; Keratin; Knowledge; Laboratories; Link; Malignant Neoplasms; Medical; Medical Genetics; Medical center; Membrane Transport Proteins; Metabolic; Metastatic Pheochromocytoma; Methods; Molecular; Molecular Biology; Molecular Genetics; Mutate; Mutation; Neck; Neoplasm Metastasis; Neuroendocrine Tumors; Neuroendocrinology; Neurosecretory Systems; Norepinephrine; Nuclear; Oncology; Outcome; Oxidation-Reduction; Oxidative Stress; Pancreas; Paraganglioma; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmacology; Phenotype; Pheochromocytoma; Play; Positioning Attribute; Professional Organizations; Prognosis; Publishing; Reporting; Research Personnel; Risk; Role; S100 Proteins; SLC11A2 gene; Societies; Succinates; Survival Rate; Tachyarrhythmias; Technology; Therapeutic; Time; Transferrin; Translational Research; Tumor Antigens; Tyrosine 3-Monooxygenase; United States National Institutes of Health; Variant; Visualization; adrenal hypertension; age group; anatomic imaging; base; cancer classification; clinical Diagnosis; clinical application; clinical practice; cohort; diagnostic biomarker; driving force; follow-up; ganglion cell; genetic disorder diagnosis; improved; in vivo; machine learning algorithm; male; meetings; metabolomics; molecular imaging; mutation carrier; novel therapeutic intervention; overexpression; oxidative DNA damage; patient oriented; patient oriented research; pediatric patients; pre-clinical; predictive modeling; prognostic; radiomics; receptor; research clinical testing; sustentacular cell; symposium; transferrin receptor 2; tumor; tumorigenesis; working group

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 PPGLs are rare in children with only a few SDHB mutation-related cases. Previous studies on children were conducted in small cohorts. This large set of pediatric patients provides robust data in the evaluation of clinical outcomes. Thirty-eight males and 26 females were diagnosed with PPGL at a median age of 13 years. The majority of patients displayed norepinephrine hypersecretion and 73.44% initially presented with a solitary tumor. Metastases developed in 70% of patients at the median age of 16 years and were mostly diagnosed first 2 years and in years 12-18 post-diagnosis. The presence of metastases at the time of diagnosis had a strong negative impact on survival in males but not in females. The estimated 5-, 10-, and 20-year survival rates were 100%, 97.14%, and 77.71%, respectively. The present report has highlighted several important aspects in the management of pediatric patients with SDHB mutations associated-PHEO/PGL. Initial diagnostic evaluation of SDHB mutation carriers should be started at age of 5-6 years with initial work-up focusing on abdominal region. Thorough follow-up is crucial first 2 years post-diagnosis and more frequent follow-ups are needed in years 10-20 post-diagnosis due to the increased risk of metastases. Although this age group developed metastasis as early as 5 years from diagnosis, we have shown that the overall 20-year prognosis and survival are good. Distinction of PPGL from epithelial neuroendocrine tumors (NETs) can be difficult as they can mimic each other by nested architecture and expression of neuroendocrine markers. In this study, we examined differential diagnostic markers in 262 PPGLs (142 adrenal pheochromocytomas and 120 extra-adrenal PGLs), 9 duodenal gangliocytic PGLs and 3 cauda equina PGLs, and 286 NETs. While keratin expression was nearly uniform in NETs with the exception of few tumors, extensive keratin expression was seen in only one PGL . GATA3 was present in >90% of PGLs but only in 2% of NETs, usually focally. Tyrosine hydroxylase (TH) was expressed in >90% of adrenal, abdominal, and thoracic PGLs but only in 37% of head and neck PGLs, TH-expression was detected in 10% of NETs. CDX2 was a helpful discriminator seen in 28% of pancreatic and most GI NETs but in no PGLs. SOX10 detected sustentacular cells in 85% of PGLs and 7% of NETs, whereas GFAP detected sustentacular cells mainly in PGLs of neck and was absent in NETs. Duodenal gangliocytic PGLs (n = 9) and all cauda equina PGLs (n = 3) expressed keratins, lacked GATA3, showed no or minimal TH expression as some NETs, and contained SOX10 and S100 protein-positive spindle cells negative for GFAP. Ganglion-like epithelioid cells were keratin-positive and negative for TH and SOX10 differing from true ganglion cells. We conclude that duodenal gangliocytic and cauda equina PGLs have a NET-like immunoprofile and differ from ordinary PGLs. NETs can be distinguished from PGLs by their expression of keratins and general lack of GATA3, TH, and GFAP-positive sustentacular cells, and sometimes by expression of CDX2 or TTF1. We also introduced algorithms for optimal management in catecholamine-induced tachyarrhythmias and published a position statement and consensus of the Working Group of Endocrine Hypertension of the European Society of Hypertension. Imaging aspects of PPGLs Nuclear (molecular) imaging plays a central role in oncology by allowing in vivo visualization of molecular dysregulation as well as overexpression of certain cell membrane transporters, receptors, or tumor antigens (1). There are multiple ways to analyze data emerging from this technology: descriptivewhich occurs in routine clinical practice; quantitativeor radiomics, which provides prognostic, predictive, and companion biomarkers; integrativewhich is linked with molecular genetics; and conceptualwhich aims to advance and expand the nosologic classification of cancers. Rapid advances in technology and artificial intelligence (AI) are already affecting these aspects and leading to a convergence of each dimension. In this study we have introduced how to approach PPGLs using multiple approaches analyzing data from anatomic and functional imaging. In another study we highlighted current relationship between genotypes and molecular imaging phenotypes. Additionally, we also summarized the referral guidelines for imaging of PPGL patients with or without knowledge of their genetic background. Metabolic aspects of PPGLs Here we compared SDHB-immunohistochemistry with metabolite profiling in 189 tumors from 187 PPGL patients. Besides evaluating succinate:fumarate ratios (SFRs), machine learning algorithms were developed to establish predictive models for interpreting metabolite data. Metabolite profiling showed higher diagnostic specificity compared to SDHB-immunmohistochemistry (99.2% versus 92.5%, p = 0.021), whereas sensitivity was comparable. Application of machine learning algorithms to metabolite profiles improved predictive ability over that of the SFR, in particular for hard-to-interpret cases of head and neck PGLs . Importantly, the combination of metabolite profiling with SDHB-immunohistochemistry has complementary utility, as SDHB-immunohistochemistry correctly classified all but one of the false negatives from metabolite profiling strategies, while metabolite profiling correctly classified all but one of the false negatives/positives from SDHB-immunohistochemistry. From 186 tumours with confirmed status of SDHx variant pathogenicity, the combination of the two methods resulted in 185 correct predictions, highlighting the benefits of both strategies for patient management. Therapeutic aspects of PPGLs: By investigating PPGL cells with low SDHB levels, we show that pseudohypoxia resulted in elevated expression of iron transport proteins, including transferrin (TF), transferrin receptor 2 (TFR2), and the divalent metal transporter 1 (SLC11A2; DMT1), leading to iron accumulation. This iron overload contributed to elevated oxidative stress. Ascorbic acid at pharmacologic concentrations disrupted redox homeostasis, inducing DNA oxidative damage and cell apoptosis in PPGL cells with low SDHB levels. Moreover, through a preclinical animal model with PPGL allografts, we demonstrated that pharmacologic ascorbic acid suppressed SDHB-low metastatic lesions and prolonged overall survival. We concluded that the data here demonstrated that targeting redox homeostasis as a cancer vulnerability with pharmacologic ascorbic acid is a promising therapeutic strategy for SDHB-mutated PPGLs. We also demonstrated a novel therapeutic strategy of targeting the NRF2-driven glutathione pathway agains

本节正在进行有关病因，流行病学，病理生理学，遗传学，诊断和治疗嗜铬细胞瘤和paraganglioma（PPGL）的研究。项目不仅包括将基础科学知识应用于临床诊断，病理生理学和治疗，还包括反向翻译研究，对临床发现的欣赏会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，本节的策略基于NIH调查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基准级组件链接在一起。目前，面向患者的成分（医学神经内分泌学）是我们假设和发现的主要驱动力。两个基准级成分（肿瘤发病机理，遗传学，化学和生物标志物以及实验性免疫疗法）首先强调，这是针对途径和靶标发现的基础研究的技术，第二，第二，将发现的发展开发到临床应用中。 PPGL的临床和遗传方面 在只有几个与SDHB突变相关病例的儿童中，PPGL很少见。先前对儿童的研究是在小型队列中进行的。这组大量的儿科患者在评估临床结果时提供了强大的数据。 38名男性和26名女性在中位年龄为13岁。大多数患者表现出去甲肾上腺素的过度分泌，最初出现73.44％的患者。在16岁的中位患者中，有70％的患者发生转移，大多数被诊断出头2年，在诊断后12 - 18年中。诊断时转移的存在对男性的存活情况有很大的负面影响，但在女性中却没有强烈的负面影响。估计的5、10和20年生存率分别为100％，97.14％和77.71％。本报告强调了与pheo/pgl相关的SDHB突变患者管理的几个重要方面。 SDHB突变载体的初始诊断评估应在5-6岁时开始，最初的锻炼重点是腹部区域。彻底的随访是在诊断后至关重要的两年，由于转移风险增加，在10 - 20年诊断中需要更频繁的随访。尽管该年龄段最早从诊断开始了5年，但我们已经表明，整体20年的预后和生存良好。 PPGL从上皮神经内分泌肿瘤（NET）的区别可能很困难，因为它们可以通过嵌套结构和神经内分泌标记的表达相互模仿。在这项研究中，我们检查了262个PPGL（142个肾上腺嗜铬细胞瘤和120个肾上腺外PGLS）的鉴别诊断标记物，9个十二指肠神经节PGL和3个Cauda Equina equina equina equina PGLS和286个网。虽然角蛋白的表达在网中几乎均匀，但较少的肿瘤除外，仅在一个PGL中看到了广泛的角蛋白表达。 GATA3在> 90％的PGL中存在，但仅在2％的网中，通常是局部。酪氨酸羟化酶（Th）在> 90％的肾上腺，腹部和胸腔PGL中表达，但仅在37％的头颈PGL中表达，在10％的网中检测到TH-表达。 CDX2是28％的胰腺和大多数GI网中看到的有用的歧视者，但没有PGL。 Sox10在85％的PGL和7％的网中检测到固定细胞，而GFAP检测到的固定细胞主要在颈部PGL中，网中没有。十二指肠神经节PGL（n = 9）和所有Cauda Equina PGLS（n = 3）表达的角蛋白缺乏GATA3，没有表现为某些网，并包含Sox10和S100蛋白质阳性蛋白质蛋白链球细胞为GFAP的阴性。神经节上皮细胞是角蛋白阳性的，对于与真正的神经节细胞不同的Th和Sox10。我们得出的结论是，十二指肠神经节和尾部pgls具有净样免疫元素，与普通PGL不同。网络可以通过PGL来区分它们的角蛋白表达以及GATA3，TH和GFAP阳性稳态细胞的总体缺乏，有时通过CDX2或TTF1的表达来区分。 我们还介绍了Catecholamine诱导的心律失常的最佳管理算法，并发表了欧洲高血压社会内分泌高血压工作组的立场声明和共识。 pPGL的成像方面 核（分子）成像在肿瘤学中起着核心作用，通过允许体内可视化分子失调以及某些细胞膜转运蛋白，受体或肿瘤抗原的过表达（1）。有多种方法可以分析从这项技术中出现的数据：在常规临床实践中发生的描述性；定量放射素学，可提供预后，预测性和伴随生物标志物；与分子遗传学有关的综合性；和旨在促进和扩展癌症的疾病分类的概念。技术和人工智能（AI）的快速进步已经在影响这些方面，并导致每个维度的融合。在这项研究中，我们介绍了如何使用多种方法来分析来自解剖和功能成像的数据的多种方法。在另一项研究中，我们强调了基因型与分子成像表型之间的当前关系。此外，我们还概述了具有或不知道其遗传背景的PPGL患者成像的转介指南。 PPGL的代谢方面 在这里，我们比较了SDHB-免疫组织化学与来自187名PPGL患者的189个肿瘤的代谢产物分析。除了评估琥珀酸酯：富马酸酯比（SFR）外，还开发了机器学习算法，以建立解释代谢物数据的预测模型。与SDHB-免疫组织化学（99.2％对92.5％，p = 0.021）相比，代谢产物分析显示出更高的诊断特异性，而灵敏度是可比的。机器学习算法在代谢物概况上的应用提高了SFR的预测能力，尤其是针对头颈部PGL的困难释放案例。 Importantly, the combination of metabolite profiling with SDHB-immunohistochemistry has complementary utility, as SDHB-immunohistochemistry correctly classified all but one of the false negatives from metabolite profiling strategies, while metabolite profiling correctly classified all but one of the false negatives/positives from SDHB-immunohistochemistry.从186个SDHX变异致病状态确认状态的肿瘤中，两种方法的组合产生了185个正确的预测，突出了两种策略在患者管理中的益处。 PPGL的治疗方面： 通过研究较低的SDHB水平的PPGL细胞，我们表明假蛋白氧化导致铁转运蛋白的表达升高，包括转铁蛋白（TF），转移蛋白受体2（TFR2）和二价金属转运蛋白1（SLC11A2； DMT1），导致铁的积累。这种铁超负荷导致氧化应激升高。药理学浓度下的抗坏血酸破坏了氧化还原稳态，诱导SDHB水平低的PPGL细胞中DNA氧化损伤和细胞凋亡。此外，通过带有PPGL同种异体移植的临床前动物模型，我们证明了药物抗坏血酸抑制了SDHB-LOW转移性病变并延长了总体存活率。我们得出的结论是，此处的数据表明，用药理学抗坏血酸将氧化还原稳态作为癌症脆弱性是SDHB突破性PPGLS的一种有前途的治疗策略。 我们还展示了针对NRF2驱动的谷胱甘肽途径的新型治疗策略