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.

嗜铬细胞瘤是一种罕见但临床上重要的嗜铬细胞瘤，可通过手术纠正慢性高血压的病因。嗜铬细胞瘤的临床特征和后果是由肿瘤释放儿茶酚胺（如去甲肾上腺素和肾上腺素）引起的。在我们的方案研究中，我们想知道血浆肾上腺素的测量是否是诊断肿瘤最敏感的生化测试，以及氟多巴胺正电子发射断层扫描（PET）是否会提高我们定位嗜铬细胞瘤的能力。此外，我们希望发现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、恶性潜能和复发。迄今为止，40例已知或临床怀疑嗜铬细胞瘤的患者在静脉注射6-[18F]氟多巴胺后进行了PET扫描。[18F]氟多巴胺使28例患者的肿瘤局部化。所有血浆肾上腺素水平正常的患者都有6-[18F]氟多巴胺PET扫描为阴性。由此得出结论，6-[18F]氟多巴胺PET扫描可以在已知存在肿瘤的患者中检测并定位嗜铬细胞瘤。考虑肿瘤但因血浆肾上腺素阴性而被排除的患者，其6-[18F]氟多巴胺PET扫描结果为阴性。这些初步发现证明6-[18F]氟多巴胺PET扫描可作为诊断工具。在我们迄今为止的生化诊断研究中，血浆肾上腺素的敏感性为99%，特异性为90%。新的氯吡啶试验结合血浆肾上腺素的测量是最有希望排除嗜铬细胞瘤患者出现类似肿瘤存在的症状的试验。RET原癌基因的遗传突变在2型多发性内分泌肿瘤患者中具有致瘤性。然而，目前尚不清楚为什么只有目标器官中少数受影响的细胞发展成肿瘤。对5例无亲缘关系的men2患者的9例嗜铬细胞瘤的遗传分析显示，10三体中RET突变等位基因的重复或野生型RET等位基因的缺失。通过突变等位基因的重复或野生型等位基因的缺失，我们的研究结果表明，“二次打击”导致突变RET等位基因的显性效应可能是MEN 2患者嗜铬细胞瘤发生的机制。最后，我们的实验室目前正在尝试建立嗜铬细胞瘤细胞培养，并使用微阵列分析等新技术来追溯肿瘤的表型差异，以潜在的基因表达差异，并最终追溯到导致肿瘤的基本体细胞或种系突变。