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. A minority of patients with Cushing's disease recur after successful transsphenoidal surgery. We studied whether patients with subnormal postoperative cortisol (2-4.9 μg/dl) might achieve long-term remission and whether the postoperative responses to CRH might predict recurrence. We prospectively studied CD patients with initial remission after adenomectomy or hemihypophysectomy (n = 14). Long-term recurrence (n = 39) or remission (n = 293) was assigned by laboratory results, glucocorticoid dependence, or patient survey at a mean of 10.6 yr after surgery. Postoperatively, morning cortisol was measured on d 3-5, and cortisol and ACTH responses to ovine CRH were assessed around d 10. Patients were followed for a median of 11 yr. Fewer patients achieved a cortisol nadir below 2 μg/dl (87%) than below 5 μg/dl (98%), yet recurrence rates were similar (<2 μg/dl, 9.5%;<5 μg/dl, 10.4%;2-4.9 μg/dl, 20%;not significant). CRH-stimulated cortisol (P <0.002) and ACTH (P = 0.04) values were higher for the recurrence than the remission group. However, no basal or stimulated ACTH or serum or urine cortisol cutoff value predicted all who later recurred. Thus, a postoperative cortisol below 2 μg/dl predicts long-term remission after transsphenoidal surgery in CD. Remission in those with intermediate d 3-5 postoperative cortisol values (2-4.9 μg/dl) suggests that these patients do not require immediate reoperation. However, because no single cortisol cutoff value excludes all patients with recurrence, all require long-term clinical follow-up. In a retrospective study we evaluated whether the addition of prolactin measurements to IPSS sampling can aid in evaluation of whether the sampling is adequate. Twenty-five of 29 patients had a pathologically proven diagnosis (17 CD and eight EAS). IPSS results were partitioned into true positive for CD (n = 16), true negative (n = 7), false negative (n = 1), and false positive (n = 1). Prolactin IPS/P ratio suggested successful IPSS in eight of 11 with abnormal venograms. Baseline prolactin IPS/P ratio was helpful in two patients with abnormal venograms and false-negative (catheterization unsuccessful) or true-negative (catheterization successful) IPSS results;the normalized ratio correctly diagnosed their disease. Normalized ACTH IPS/P ratio was at least 1.3 in all with CD, but prolactin IPS/P ratios were misleadingly low in two. One patient with cyclic EAS had a false-positive IPSS when eucortisolemic (baseline prolactin IPS/P = 1.7;normalized ratio = 5.6). All other EAS patients had normalized ratios no higher than 0.7. We concluded that prolactin measurement and evaluation of the venogram can improve diagnostic accuracy when IPSS results suggest EAS but is not necessary with positive IPSS results. Confirmation of hypercortisolemia remains a prerequisite for IPSS. A normalized ratio of 0.7-1.3 was not diagnostic. Spontaneous remission is rare in ectopic ACTH syndrome (EAS). We described four patients with presumed EAS in whom long-term treatment with steroidogenesis inhibitors was followed by prolonged remission of hypercortisolemia. Biochemical testing was consistent with EAS, but imaging failed to identify a tumor. Patients were treated with ketoconazole alone or with mitotane and/or metyrapone to control hypercortisolemia. Dexamethasone was added when a block and replace strategy was used. Treatment with steroidogenesis inhibitors for 3-10 years in these patients was followed by a prolonged period of remission (15-60 months). During remission, the first patient had an elevated ACTH, low cortisol and 24-h urinary free cortisol (UFC), and adrenal atrophy on computerized tomography scan during remission, suggesting a direct toxic effect on the adrenal glands. Cases 2 and 3 had normal to low ACTH levels and low-normal UFC, consistent with an effect at the level of the ectopic tumor. They did not have a history of cyclicity and case 3 has been in remission for 5 years, making cyclic Cushing's syndrome less likely. Case 4, with a history of cyclic hypercortisolism, had normal to slightly elevated ACTH levels and low-normal UFC during remission. The most likely etiology of remission is cyclic production of ACTH by the ectopic tumor. Spontaneous and sustained remission of hypercortisolemia is possible in EAS after long-term treatment with steroidogenesis inhibitors;a drug holiday may be warranted during chronic therapy to evaluate this. Context: ACTH-producing neuroendocrine tumor (NET) of the thymus is a rare cause of Cushing's syndrome (CS). We studied 12 cases (eight males and four females) diagnosed between 1986 and 2010 with CS and thymic NET who underwent surgical resection. We measured time from onset of CS to diagnosis of thymic NET, tumor size, histological grade, time to recurrence, and survival and performed a meta-analysis of other published cases of CS associated with thymic NET. Eleven of 12 patients presented with classic features of CS at a median age of 21 yr (range, 7-51). Four were children. The 24-h urine free cortisol was greater than 16-fold of normal, and biochemical testing was consistent with ectopic ACTH production in all 11. Another patient presenting with pulmonary embolus had a thymic mass and was later diagnosed with CS. All patients underwent thymectomy, and nine of 10 tumors exhibited positive ACTH immunochemistry. Median tumor diameter was 5 cm (range, 1-11.5). Six patients recurred 20-28 months after surgery with metastases to mediastinal lymph nodes (n = 5), bone (n = 5), liver (n = 1), parotid gland (n = 1), and breast (n = 1). Four of five patients treated with radiation therapy also received chemotherapy. All recurrent patients received ketoconazole;four later underwent bilateral adrenalectomy. Six recurrent patients died 22-90 months (median, 57) after thymectomy. At last review, six patients were alive 14-90 months (median, 49) after thymectomy. These data are similar to those from the meta-analysis. We conclude that thymic ACTH-producing NET is an aggressive disease that should be considered in CS with ectopic ACTH secretion, particularly in younger patients. 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. We have also observed that two individuals with a negative octreoscan initially converted that to a positive scan after mifepristone treatment.
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