Diagnosis, Pathophysiology And Molecular Biology Of Pheo

嗜铬细胞瘤是一种罕见但临床上很重要的嗜铬细胞肿瘤，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肿瘤释放儿茶酚胺(如去甲肾上腺素和肾上腺素)的结果。我们发现，血浆中代肾上腺素的测定是诊断肿瘤最敏感的生化试验。到目前为止，在我们的生化诊断研究中，血浆中间肾上腺素的敏感性为99%，特异性为90%。在出现类似肿瘤症状的患者中，新的可乐定测试结合血浆中的甲肾上腺素的测量是最有希望排除嗜铬细胞瘤的测试。我们还发现，氟多巴正电子发射断层扫描(PET)扫描提高了嗜铬细胞瘤的定位能力，它优于131-I间碘苯甲基胍核素扫描。这些发现证明6-[18F]氟多巴胺正电子发射计算机断层扫描是一种诊断工具。此外，我们正在寻找任何特定的遗传或其他标记物来预测嗜铬细胞瘤的病程、恶性潜能和复发。RET原癌基因的遗传突变在2型多发性内分泌肿瘤患者中是致癌的。然而，为什么只有少数靶器官中的受影响细胞发展成肿瘤，目前尚不清楚。对5例与男性2无关的患者的9例嗜铬细胞瘤的遗传分析显示，突变的RET等位基因在10三体中重复或野生型RET等位基因丢失。通过突变等位基因的复制或野生型等位基因的丢失，我们的结果表明，突变的RET等位基因的显性效应是男性患者嗜铬细胞瘤发生的可能机制。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，追溯到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生殖系突变。

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.