Diagnosis and Pathophysiology Of Pheochromocytoma

嗜铬细胞瘤的诊断和病理生理学

• 批准号: 6541340
• 负责人: Karel Pacak
• 金额: --
• 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/6541340
• 关键词: adolescence (12-20); catecholamines; child (0-11); chromaffin cells; clinical research; diagnosis design /evaluation; dopamine; endocrine disorder diagnosis; human subject; molecular biology; pathology; phenylethylamines; pheochromocytoma; positron emission tomography

Pheochromocytomas are rare but clinically important chromaffin cell tumors that constitute a surgically correctable cause of chronic hypertension. The clinical features and consequences of pheochromocytoma result from release of catecholamines (e.g., norepinephrine and epinephrine) by the tumor. In our protocol studies we would like to find out whether the measurement of plasma metanephrines is the most sensitive biochemical test to diagnose the tumor and whether fluorodopamine positron emission tomography (PET) scanning will improve our ability to localize a pheochromocytoma. In addition, we wish to find out if there are any specific genetic or other markers to predict the course, malignant potential, and recurrence of pheochromocytoma. To date forty patients with known or clinically suspected pheochromocytoma underwent PET scanning after i.v. injection of 6-[18F]fluorodopamine. [18F]fluorodopamine localized the tumor in 28 patients. All patients with normal plasma levels of metanephrines had negative 6-[18F]fluorodopamine PET scans. This concludes that 6-[18F]Fluorodopamine PET scanning can detect and localize pheochromocytomas in patients known to harbor the tumor. Patients in whom the tumor is considered but excluded because of negative plasma metanephrine results have negative 6-[18F]fluorodopamine PET scans. These preliminary findings justify 6-[18F]fluorodopamine PET scanning as a diagnostic tool. In our studies of biochemical diagnosis to date, plasma metanephrines had a sensitivity of 99% and specificity of 90%. The new cloidine test coupled with the measurement of plasma metanephrines is the most promising test to rule out pheochromocytoma in patients presenting with symptoms that resemble the presence of the tumor. Inherited mutations of the RET protooncogene are tumorigenic in patients with multiple endocrine neoplasia type 2. However, it is not understood why only a few of the affected cells in the target organs develop into tumors. Genetic analysis of 9 pheochromocytomas from 5 unrelated patients with MEN 2 showed either duplication of the mutant RET allele in trisomy 10 or loss of the wild-type RET allele. Through either duplication of the mutant allele or loss of the wild-type allele, our results suggest a "second hit" causing a dominant effect of the mutant RET allele as a possible mechanism for pheochromocytoma tumorigenesis in patients with MEN 2. Finally, our laboratory is currently attempting to establish pheochromocytoma cell cultures and used new techniques such as microarray analysis to trace back phenotypic differences in tumors to underlying differences in gene expression and ultimately to the basic somatic or germline mutations responsible for the tumor.

嗜铬细胞瘤很少见，但临床上重要的铬蛋白细胞肿瘤构成了慢性高血压的手术正确原因。嗜铬细胞瘤的临床特征和后果是由肿瘤释放（例如去甲肾上腺素和肾上腺素）引起的。在我们的协议研究中，我们希望找出血浆替甲肾上腺素的测量是诊断肿瘤的最敏感的生化测试，以及氟二哌二甲胺正电子发射断层扫描（PET）扫描是否会提高我们局部定位植变型肉瘤的能力。此外，我们希望找出是否有任何特定的遗传或其他标记来预测嗜铬细胞瘤的病程，恶性潜力和复发。迄今为止，有40例已知或临床怀疑的嗜铬细胞瘤患者在静脉注射后接受了PET扫描。注射6- [18F]氟迪帕胺。 [18F]氟二甲胺在28例患者中局部肿瘤。所有血浆水平正常的替甲肾上腺素水平的患者均为6- [18F]氟二胺PET扫描。这得出的结论是，6- [18F]氟二胺PET扫描可以检测并定位已知含有肿瘤的患者的嗜铬细胞瘤。考虑到肿瘤的患者因血浆负阴性而被排除在外，结果为6- [18F]氟二胺PET扫描。这些初步发现证明了6- [18F]氟二胺PET扫描作为诊断工具。在我们迄今为止的生化诊断研究中，血浆替代肾上腺素的敏感性为99％，特异性为90％。新的链球菌测试以及血浆倍肽的测量是排除症状类似于肿瘤存在的症状的患者的最有前途的测试。多种内分泌肿瘤2型患者的RET原子量的遗传突变是肿瘤性的。但是，尚不理解为什么仅靶器官中只有少数受影响的细胞会发展为肿瘤。对5例男子2患者的9个嗜铬细胞瘤的遗传分析表明，三体术中突变体RET等位基因的重复或野生型RET等位基因的丧失。 Through either duplication of the mutant allele or loss of the wild-type allele, our results suggest a "second hit" causing a dominant effect of the mutant RET allele as a possible mechanism for pheochromocytoma tumorigenesis in patients with MEN 2. Finally, our laboratory is currently attempting to establish pheochromocytoma cell cultures and used new techniques such as microarray analysis to trace back phenotypic differences in tumors基因表达的潜在差异，并最终与负责肿瘤的基本体细胞或种系突变。