Diagnosis, Pathophysiology And Molecular Biology Of Pheo

嗜铬细胞瘤是一种罕见但临床上重要的嗜铬细胞肿瘤，它是慢性高血压的一个可手术矫正的病因。嗜铬细胞瘤的临床特征和后果是由儿茶酚胺的释放引起的（例如，去甲肾上腺素和肾上腺素）。我们发现血浆变肾上腺素的测量是诊断肿瘤的最敏感的生化试验。在我们迄今为止的生化诊断研究中，血浆变肾上腺素的敏感性为99%，特异性为90%。新的可乐定试验结合血浆变肾上腺素的测量是最有希望的试验，以排除嗜铬细胞瘤的患者表现出类似于肿瘤的存在症状。我们还发现，氟多巴正电子发射断层扫描（PET）扫描提高了定位嗜铬细胞瘤的能力，它是上级131-碘间苄胍造影。这些发现证明6-[18F]氟多巴PET扫描作为诊断工具是合理的。此外，我们正在寻找任何特定的遗传或其他标记来预测嗜铬细胞瘤的过程，恶性潜力和复发。RET原癌基因的遗传性突变在多发性内分泌腺瘤病2型患者中具有致瘤性。然而，目前还不清楚为什么靶器官中只有少数受影响的细胞发展成肿瘤。对来自5名不相关MEN 2患者的9例嗜铬细胞瘤的遗传分析显示，要么在10三体中重复突变RET等位基因，要么丢失野生型RET等位基因。通过突变等位基因的重复或野生型等位基因的丢失，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，作为MEN 2患者嗜铬细胞瘤肿瘤发生的可能机制。最后，我们的实验室目前正试图建立嗜铬细胞瘤细胞培养，并使用新技术，如微阵列分析，以追溯肿瘤的表型差异，潜在的基因表达差异，并最终到负责肿瘤的基本体细胞或种系突变。

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. We found that the measurement of plasma metanephrines is the most sensitive biochemical test to diagnose the tumor. In our studies of biochemical diagnosis to date, plasma metanephrines had a sensitivity of 99% and specificity of 90%. The new clonidine 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. We also found that fluorodopamine positron emission tomography (PET) scanning improves the ability to localize a pheochromocytoma and it is superior to 131-I metaiodobenzylguanidine scintigraphy. These findings justify 6-[18F]fluorodopamine PET scanning as a diagnostic tool. In addition, we are searching for any specific genetic or other markers to predict the course, malignant potential, and recurrence of pheochromocytoma. 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.