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