The differential diagnosis and treatment of Cushing's syndrome

在由促肾上腺皮质激素(ACTH)分泌异位引起的库欣综合征患者中，影像研究是肿瘤定位的基石。计算机断层扫描(CT)和磁共振成像(MRI)最常用于定位EAS的来源。然而，在30-50%的EAS患者中，尽管经过反复研究，仍无法找到ACTH的分泌来源。其中多达一半的患者对皮质醇增多症的药物治疗没有反应，必须接受双侧肾上腺切除术和终身替代疗法。因此，需要改进的成像技术来识别分泌ACTH的肿瘤。 核医学技术能够对生理和病理生理过程进行活体成像，其中正电子发射断层扫描(PET)技术在肿瘤学中的应用越来越多。我们先前评估了高于标准剂量的18F-脱氧葡萄糖(FDG)正电子发射断层扫描(PET)或111In-DTPA-D-Phe-五核苷酸(OCT)的应用价值，发现FDG-PET不能发现CT/MRI上隐匿的肿瘤。H-OCT很少发现病变。因此，应使用常规的CT和MRI方法对这些患者的颈部、胸部和腹部进行成像。FDG-PET不提供额外的信息。当其他成像手段无法定位分泌ACTH的肿瘤时，H-OCT可能有用。 目前，我们正在扩展这些研究，以评估18F-L-3，4-二羟基苯丙氨酸(18F-DOPA)PET对这些肿瘤的诊断价值。这种化合物是神经内分泌肿瘤产生5-羟色胺的前体，因此是PET检查的一个很好的候选对象，因为大多数隐匿性的ACTH分泌肿瘤是神经内分泌的。 在一项前瞻性的先导性研究中，我们还评估了血清CGA、CT、ProCT或NProCT值是否能区分CD和EAS。对IPSS诊断的6例隐匿性EAS患者、25例CD患者和11例经组织学证实的EAS患者的血清ProCT、NProCT和CGA进行了检测。9例EAS患者(53%)至少有一个高于参考范围，包括CGA(n=4)、ProCT(n=3)、CGA+ProCT(n=1)和NProCT+ProCT(n=1)。在9例(36%)CD患者中，7例仅有ProCT升高，1例仅NProCT升高，1例CGA和ProCT升高。CgA对EAS诊断的阳性预测值为83%，阴性预测值为70%，其他标志物对EAS的鉴别能力较差。在垂体磁共振成像上，无一例EAS患者出现异常，而25例CD患者中有21例有肿块。这些初步结果表明，CGA异常和正常的垂体磁共振成像有助于EAS的诊断，但正常的肿瘤标志物不能排除诊断。 虽然用磁共振成像(MRI)检测脑垂体瘤可以降低库欣病患者的诊断成本并改善手术结果，但最佳的T1加权自旋回波MRI方案仍不清楚。我们假设特定的MR扫描参数会影响促肾上腺皮质激素瘤的发现。我们发现，连续84例库欣病患者中，有21例在最初的脑垂体MRI检查中假阴性，随后在NIH临床中心发现了一个病变。在18名可用扫描的患者中，矩阵大小相似，几乎所有患者的层厚均为3 mm。NIH与外部扫描的不同参数为：RR(400ms比492+/-19ms，P=0.0002)；TE(10.3+/-0.5ms比17.2ms+/-1.2ms，P=0.0003)；视野(12x12 cm比17+/-0.6x18+/-0.7 cm，P&lt；0.0001)。经蝶窦手术切除的肿瘤免疫组织化学证实均为促肾上腺皮质激素瘤。我们得出结论，MRI技术，特别是FOV和TR/TE值会影响结果，并建议内分泌学家在解释结果时考虑垂体部MRI参数。 糖皮质激素拮抗剂米非司酮可阻断皮质醇的作用，因此可能是治疗库欣综合征的有效药物。这一假设正在一项正在进行的临床试验中得到验证，该试验针对假定为异位ACTH分泌的患者。

Imaging studies are the cornerstone for tumor localization in patients with Cushing's syndrome caused by ectopic adrenocorticotropin hormone (ACTH) secretion (EAS). Computed tomography (CT) and magnetic resonance imaging (MRI) are used most commonly to localize the source of EAS. However, in 30-50 percent of patients with EAS the source of ACTH secretion cannot be found despite repeated studies over time. Up to half of these patients do not respond to medical therapy of hypercortisolism and must undergo bilateral adrenalectomy with lifelong replacement therapy. Thus, there is a need for improved imaging techniques to identify ACTH-secreting tumors. Nuclear medicine techniques enable in vivo imaging of physiological and pathophysiological processes, and among these techniques, positron emission tomography (PET) studies are increasingly used in oncology. We previously evaluated the utility of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) or 111In-DTPA-D-Phe-pentetreotide (OCT) at higher than standard doses of radionuclide (18 mCi; H-OCT), and found that FDG-PET did not detect tumors that were occult on CT/MRI. H-OCT rarely identified a lesion. Thus, conventional modalities of CT and MRI should be used to image the neck, thorax, and abdomen in these patients. FDG-PET does not provide additional information. H-OCT may be useful when other imaging modalities fail to localize the ACTH-secreting tumor. Currently we are extending these studies to evaluate the utility of 18F- L-3,4-dihydroxyphenylalanine (18F-DOPA) PET to identify these tumors. This compound is a precursor for serotonin production in neuroendocrine tumors, and thus is a good candidate for PET examination since most occult ACTH-secreting tumors are neuroendocrine. We have also evaluated whether serum CgA, CT, ProCT, or NProCT values to distinguish CD from EAS in a prospective pilot study. Serum ProCT, NProCT, and CgA were measured in six patients with occult EAS diagnosed by IPSS, 25 CD patients, and 11 patients with histologically proven EAS. Nine EAS patients (53%) had at least one value above the reference range, including CgA alone (n = 4), ProCT alone (n = 3), CgA and ProCT (n = 1), and NProCT and ProCT (n = 1). Of nine (36%) CD patients with one or two abnormal values, seven had increased ProCT only, one had increased NProCT only, and one had increased CgA and ProCT. CgA had a positive predictive value of 83% and a negative predictive value of 70% for the diagnosis of EAS; other markers showed less discrimination. On pituitary magnetic resonance imaging, no EAS patient had an abnormality, whereas 21 of 25 patients with CD had a mass. These preliminary results suggest that an abnormal CgA and normal pituitary magnetic resonance imaging favor the diagnosis of EAS, but normal tumor markers do not exclude the diagnosis. While detection of pituitary tumors with magnetic resonance imaging (MRI) may reduce diagnostic costs and improve surgical outcomes for patients with Cushing's disease, the optimal T1-weighted spin echo MRI protocol remains unknown. We hypothesized that specific MR scanning parameters influence detection of corticotropinomas. We found that 21 of 84 consecutive patients with Cushing's disease had a falsely negative initial pituitary MRI study and a lesion identified subsequently at the NIH Clinical Center. In 18 patients with available scans, matrix sizes were similar and nearly all had 3 mm slice thickness. Parameters that differed between the NIH and outside scans were: TR (400 ms vs. 492+/-19 ms, P = 0.0002); TE (10.3 +/- 0.5 vs. 17.2 ms +/- 1.2 ms, P = 0.0003); FOV (12x12 cm vs.17+/-0.6 x 18+/-0.7 cm, P<0.0001). Immunohistochemistry of tumors resected at transsphenoidal surgery confirmed all to be corticotropinomas. We conclude that MRI technique, particularly FOV and TR/TE value, influences results and recommend that endocrinologists consider pituitary MRI parameters when interpreting the results. The glucocorticoid antagonist mifepristone blocks cortisol action and thus might be an effective treatment of Cushing's syndrome. This hypothesis is being tested in an ongoing clinical trial of patients with presumed ectopic ACTH secretion.