岩下窦静脉取血在疑难ACTH依赖性库欣综合征诊断中的应用

目的 探讨岩下窦静脉取血(IPSS)在疑难库欣综合征诊断中的价值.方法 对20例疑难库欣综合征行岩下窦和外周静脉取血,测定血ACTH浓度比,评价其对库欣病诊断的敏感性和特异性.结果 18例患者的岩下窦与外周静脉血ACTH的比值＞2,其中13例行经蝶窦垂体术后病理为垂体ACTH腺瘤;1例行鞍区γ-刀治疗、4例行生长抑素治疗后病情缓解.2例岩下窦与外周静脉血ACTH的比值＜2,其中1例为右肺类癌,另1例为垂体ACTH腺瘤.本组IPSS诊断库欣病的敏感性和特异性分别为93%和100%.结论 IPSS操作安全,并发症少,可作为疑难库欣综合征的重要鉴别方法.     

经蝶窦显微外科手术治疗541例库欣病

目的 探讨经蝶窦入路显微外科手术治疗库欣病的疗效。方法 总结北京协和医院神经外科1981年至2007年收治的541例库欣病的临床资料。结果CT和（或）MRI显示微腺瘤、大腺瘤、巨大腺瘤和未见异常的比例分别为66.2％( 358/541)、14.0％( 76/541)、0.6％( 3/541)和19.2％(104/541)。病理为垂体ACTH腺瘤、增生和既未见肿瘤又未见增生的比例分别为75.4％(408/541)、8.3％ (45/541)和16.3％ (88/541)。病理明确腺瘤、增生以及病理阴性者术后近期（半年内）治愈率分别是85.0％( 347/408)、24.4％ (11/45)和45.5％(40/88)。随访0.5 -25.0年（平均3.1年）,复发率13.3％(53/398),复发时间0.5 -16.5年（平均3.4年）。结论 经蝶窦选择性垂体腺瘤切除加瘤周垂体组织大部分切除是治疗库欣病安全有效的首选方法。对首次手术无效或复发性库欣病,可以再次经蝶窦手术或垂体放疗。     

Pituitary corticotroph hyperplasia preceding adenoma in a patient with Nelson's syndrome

We report the case of a 42-year-old woman with Cushing's disease and Nelson's syndrome. When she was 17 years old, transsphenoidal surgery was performed. A detailed morphologic study demonstrated nodular hyperplasia of corticotroph cells but no adenoma. Following a long-lasting remission (14 years), Cushing's disease recurred. After an unsuccessful second transsphenoidal surgery, Cushing's disease persisted and both adrenals were removed (at the age of 34). Subsequently the patient developed Nelson's syndrome. The pituitary tumor proved to be a corticotroph adenoma; it was removed by the transsphenoidal approach (at the age of 42). Although in most patients Cushing's disease is due to an ACTH-secreting pituitary corticotroph adenoma which precedes the manifestation of Nelson's syndrome, our case indicates not only that corticotroph hyperplasia may cause Cushing's disease but that it may exist before the development of Nelson's syndrome after the removal of both adrenals. Our study supports the view that protracted stimulation of corticotrophs resulting from the elimination of the negative inhibitory feedback effect by corticosteroids plays a role in adenoma initiation.     

Severe myopathy and psychosis in a patient with Cushing's disease macroadenoma

Cushing's disease is most commonly caused by a corticotrope adenoma of the pituitary. Between 50 and 70% of patients with spontaneous hypercortisolism have ACTH-producing pituitary adenomas. The tumors are usually microadenomas with approximately 20% of patients with the disease showing no evidence of tumor on CT-scans or MR imaging of their pituitary glands. In contrast to patients with ectopic ACTH production, plasma ACTH concentrations in patients with spontaneous disease are generally within the normal range. We describe here a patient with a pituitary macroadenoma that showed evidence of necrosis on MRI. The patient had an atypical clinical presentation with plasma ACTH levels considerably higher than that seen in patients with non-ectopic ACTH-secretory syndrome, markedly elevated urine free cortisol, lack of phenotypical signs of hypercortisolism such as wide purplish striae, and whose most prominent and distressing symptom was severe myopathy that resulted in the patient becoming bed-ridden. Psychosis was another striking feature in this patient who during his hospital course developed multiple opportunistic infections that contributed to his demise.     

Corticotropin-releasing factor (CRF): stimulation in normal controls and in patients with Cushing's syndrome

Synthetic ovine and human CRF were given as an i.v. bolus to six healthy volunteers in four and two different dosages, respectively (oCRF: 25, 50, 100 and 200 micrograms; hCRF: 50 and 100 micrograms). There was a significant increase of ACTH and cortisol after the injection of all dosages though the dose-response relationship was only significant between the 50 and 100 micrograms dose of oCRF. No significant differences between ACTH and cortisol secretion after oCRF and hCRF were observed. Repetitive stimulation by hCRF led to repetitive release of identical amounts of ACTH. The CRF test with the 100 micrograms dosage was used in patients with proven Cushing's syndrome (n = 30). Results showed that the CRF test is useful in making the differential diagnosis of established Cushing's syndrome. In patients with ACTH-dependent Cushing's disease (n = 21), normal or elevated basal ACTH levels were significantly higher after stimulation by CRF compared to normal controls, with one exception. The pattern of cortisol secretion after CRF administration corresponded to the pattern of ACTH secretion in these patients. In two patients with ectopic ACTH syndrome, extremely elevated ACTH and cortisol levels did not change or showed only a small increase after CRF administration. In patients with unilateral adrenal adenoma or carcinoma (n = 7), suppressed ACTH levels did not rise after CRF administration. In addition, no significant change in cortisol secretion could be observed. After surgical removal of cortisol-producing adrenal tumors, the ACTH response to CRF can be demonstrated when cortisol levels are still undetectable. Pulsatile administration of CRF in one patient after unilateral adrenalectomy revealed that ACTH responses to CRF normalize rapidly but cannot be sustained if CRF administration is withdrawn, suggesting that the cause of adrenal failure after unilateral adrenalectomy for Cushing's syndrome or with long-term corticoid therapy is due to hypothalamic CRF deficiency. The suppression of ACTH responses to CRF in glucocorticoid-treated patients correlated with the daily corticoid dosage. Since the ACTH hyper-response to CRF in six patients with Cushing's disease was suppressed by short-term dexamethasone treatment, the pituitary as a target site for feedback inhibition also was demonstrated.     

Management of ACTH-secreting supradiaphragmatic adenomas

Supradiaphragmatic adrenocorticotropic hormone (ACTH) secreting pituitary adenomas are exceptionally encountered (14 cases previously described) and raise issues concerning their nosology and management. If surgery is the treatment of choice, the nature of surgical approach (craniotomy, transsphenoidal approach) remains controversial. To illustrate this issue, we presented two cases of supradiaphragmatic ACTH secreting pituitary adenomas successfully excised via a subfrontal approach. Both patients were female (20 and 41 years) and had a typical Cushing's syndrome. MRI revealed, in both cases, a suprasellar mass in contact with the pars tuberalis of the pituitary. In the first case, the patient underwent initially a transsphenoidal approach with negative exploration and subsequent partial hypophysectomy. One year later, the patient was operated on again via a subfrontal approach, allowing excision of a supradiaphragmatic adenoma and a complete cure of Cushing's disease. In the second case, the patient underwent initially a subfrontal approach and was definitely cured. In both cases, the diaphragma sellae was found to be intact and the pituitary stalk could be preserved. Postoperative MRI demonstrated a clearly visible intact pituitary stalk in conjunction with normal aspect of the pituitary. Supradiaphragmatic pituitary adenomas are most likely adenomas of the pituitary stalk with extra-axial development. Surgery remains the treatment of choice. Should the superior approach be preferred, the transsphenoidal-transtuberculum sellae approach may represent a viable alternative when performed by a well-trained surgical team. Surgery may be difficult, and drawbacks are non negligible, particularly in elderly patients. In these cases, stereotactic radiosurgery should receive more consideration.     

Pituitary apoplexy due to mucormycosis infection in a patient with an ACTH producing pulmonary tumor.

Rhinocerebral mucormycosis is an acute, fulminating form of invasive fungal sinusitis occurring principally in individuals who are immunologically or metabolically compromised. The incidence of pituitary apoplexy ranges from 6% to 17%, presenting as a capsule rupture in up to 1.7-2.0%. Isolated cases of mucormycosis are associated with solid tumors and Cushing's syndrome. A 42-year-old, diabetic woman, with Cushing's syndrome of 5 years duration presented with hemiplexy, hemiparesis and altered speech following a syncopal episode and fall. Brain CT scan showed a left temporal lobe infarction. The patient deteriorated rapidly and she died 4 days later. Autopsy findings included: plurihormonal pituitary adenoma with extension to the sphenoid bone and sellar erosion; many thick, septated, mucormycosis hyphae; and recent fronto-temporal brain infarction. Also, a solitary adrenal corticotropic hormone (ACTH)-producing neuroendocrine tumor, 3 cm in diameter, was found in the left lung. This patient illustrates the correlation between ACTH-producing ectopic pulmonary tumor, pituitary apoplexy and mucormycosis.     

儿童和青春期库欣病的诊断和治疗

目的 讨论20岁以下儿童和青春期库欣病的诊断和治疗。方法 男性11例，女性23例，平均年龄15.2岁，平均病程2.1年，表现库欣综合征占91.2%，内分泌学检查符合库欣病占70.6%。CT阳性率57.1%。MRI阳性率70%，均行经蝶窦手术，术后病理证实垂体ACTH腺瘤28例。垂体增生4例，病理阴性2例。结果 随诊3个月至10年，垂体ACTH腺瘤的治愈缓解率89.3%。垂体增生和病理阴性的治疗有效率为50%。结论 经蝶窦显微外科手术是治疗库欣病的最佳方法，当内分泌学检查符合库欣病但蝶鞍MRI未发现垂体腺瘤时，或者当蝶鞍MRI发现垂体腺瘤但内分泌学检查不符合库欣病时，应行经蝶窦垂体探查术。     

Cushing's disease due to plurihormonal adrenocorticotropic hormone and gonadotropin-producing pituitary adenoma

A 67-year-old woman presented with clinical features of hypercortisolism in association with an invasive pituitary macroadenoma. Adrenocorticotropic hormone (ACTH)-dependent Cushing's disease was documented, and the resected tumor was chromophobic, weakly positive with periodic-Schiff reagent, and showed immunostaining for ACTH and beta-endorphin in a minority of adenoma cells. Both luteinizing hormone and alpha-subunit staining were also observed, but no follicle-stimulating hormone reactivity was seen. Ultrastructurally, the tumor showed typical features of a gonadotroph adenoma of female type. Immunoelectron microscopy showed that ACTH was not produced in corticotrophs, but in cells with the characteristic features of gonadotrophs. This represents the second report of a plurihormonal gonadotroph adenoma producing sufficient ACTH to result in pituitary-dependent Cushing's disease.     

伴多内分泌腺瘤病的促肾上腺皮质激素依赖性库欣综合征临床特点分析

目的 总结伴多内分泌腺瘤病(MEN)的促肾上腺皮质激素(ACTH)依赖性库欣综合征的临床特点.方法 纳入中国垂体疾病注册中心中国医学科学院北京协和医院分中心垂体瘤数据库1984年1月至2020年9月确诊的伴多内分泌腺瘤病的促肾上腺皮质激素依赖性库欣综合征患者18例,回顾分析其人口统计学、临床表现、实验室和影像学特征.结...     

Glucocorticoid receptors in anorexia nervosa and Cushing's disease.

BACKGROUND: Patients with anorexia nervosa do not display cushingoid features in spite of elevated cortisol plasma levels. Whether a cortisol resistance or a reduced availability of the metabolic substrates necessary to develop the effect of glucocorticoids is responsible for this has not been established. METHODS: Twenty-two patients with severe restrictive anorexia nervosa, 10 patients with active Cushing's disease, and 24 healthy volunteers without psychiatric disorders or mood alterations were investigated. Glucocorticoid receptor characteristics were examined on mononuclear leukocytes by measuring [3H]dexamethasone binding and the effect of dexamethasone on [3H]thymidine incorporation, which represents an index of DNA synthesis. RESULTS: The number of glucocorticoid receptors on mononuclear leukocytes (MNL) was comparable in patients with anorexia nervosa, patients with active Cushing's disease, and normal subjects (binding capacity 3.3 +/- 0.23 vs. 3.7 +/- 0.30 and 3.5 +/- 0.20 fmol/10(6) cells). Conversely, glucocorticoid receptor affinity was significantly decreased in anorexia nervosa as well as in Cushing's patients compared to control subjects (dissociation constant 4.0 +/- 0.31 and 4.1 +/- 0.34 vs. 2.9 +/- 0.29 nmol/L, p < .001) and inversely correlated with the levels of urinary free cortisol in both groups of patients. Basal [3H]thymidine incorporation in MNL was significantly reduced in anorexia nervosa as well as in Cushing's patients compared to control subjects (p < .001) and was diminished by dexamethasone to an extent similar to control subjects in patients with anorexia nervosa, but significantly (p < .001) less in those with Cushing's disease. In patients with anorexia nervosa, the incorporation of [3H]thymidine into the MNL was inversely correlated with urinary free cortisol levels. CONCLUSIONS: These data indicate that the lack of cushingoid features in patients with anorexia nervosa is not ascribable to a reduced sensitivity to glucocorticoids but is more likely due to the paucity of metabolic substrates.     

Nelson综合征的显微外科治疗(附23例报告)

目的 分析和探讨Nelson综合征的病因,诊断标准和治疗方法。方法 对我科手术治疗的23例该病病例进行回顾性研究。临床特点包括肾上腺切除手术后皮肤粘膜色素沉着,血ACTH水平升高,影像学检查发现垂体腺瘤,21例经蝶窦手术,2例经额开颅,随访时间从半年至9年,结果本组23例Nelson综合征,占同期手术治疗的库欣病的7．7％,经蝶窦手术后皮肤色素沉着减轻,血ACTH水平下降,8例视力视野障碍术后均改善,治愈率56．5％,缓解率26．1％,结论 经蝶窦垂体ACTH腺瘤切除是预防和治疗Nelson综合征的首先方法,术后应定期随访。     

垂体ACTH腺瘤的诊断和治疗(附29例报告)

目的 分析和探讨垂体ACTH腺瘤的诊断和治疗。方法 对我科收治的29例垂体ACTH腺瘤患者的临床特点和治疗效果进行了回顾性分析。结果 垂体ACTH微腺瘤的诊断较为困难，有库欣氏综合征表现的患者，辅以血清ACTH、地塞米松抑制试验等并结合影像学资料方可确诊，经蝶手术切除肿瘤复发率仅为6．9％。结论 垂体ACTH腺瘤的诊断须依靠临床表现、实验室检查和影像学检查等。经蝶手术切除肿瘤是治疗垂体ACTH腺瘤的首选方法。     

Silent mixed corticotroph and somatotroph macroadenomas presenting with pituitary apoplexy

We discuss three unique cases of pituitary macroadenoma presenting with pituitary hemorrhage but without typical endocrine symptomatology. Immunohistochemical analysis indicated positive reactivity for adrenocorticotropic hormone (ACTH) and growth hormone (GH), and in situ hybridization indicated the expression of proopiomelanocortin (POMC) and GH mRNA. We designated these cases silent mixed corticotroph and somatotroph adenoma. Patient 1 was a 30-year-old man, patient 2 was a 29-year-old woman, and patient 3 was a 59-year-old woman. All patients presented with a headache of sudden onset and visual disturbance. The patients did not exhibit typical Cushing's or acromegalic features. Serum ACTH level was remarkably elevated in patient 1, and slightly elevated in patients 2 and 3. In all patients, serum GH levels were within normal range and magnetic resonance imaging revealed an intra- and suprasellar mass with pituitary hemorrhage. Transnasal pituitary surgery in the three patients disclosed a pituitary adenoma producing ACTH and GH. In patient 2, the residual adenoma reappeared along with an intratumoral hemorrhage, and was resected by secondary transnasal surgery. Silent mixed corticotroph and somatotroph adenomas are characterized by the following: no endocrine symptoms; presentation dominated by mass effect symptoms; macroadenoma presenting with acute pituitary hemorrhage; and production of both ACTH and GH.     

Invasive Crooke cell adenoma in a patient with diffuse large B-cell lymphoma

Crooke cell adenoma (CCA) is an aggressive corticotroph subtype of pituitary adenoma often with cyclically elevated blood adrenocorticotropic hormone (ACTH), which preoperative diagnosis is challenging especially in the context of a functionally silent invasive tumor and a history of high-stage malignancy such as diffuse large B-cell lymphoma (DLBCL). Here, we report the first case of invasive CCA in a patient with DLBCL. A 71 year-old previously healthy man was recently diagnosed with DLBCL that was treated with CHOP-R chemotherapy. Within one week of completing his first cycle of chemotherapy, he had a frontal headache that progressed to right-sided proptosis. Cranial MRI showed a heterogeneously enhancing mass with invasion into the sellar and suprasellar compartment, compression of the optic chiasm, as well as extension into the clivus, bilateral cavernous sinuses, and the prepontine cistern. He underwent a partial resection for the pituitary tumor debulking. Pathological examination revealed CCA with invasion into the adjacent tissue. The patient had no history of Cushing disease or syndrome, but his blood ACTH was found to be elevated on the operation day. Our present case and literature review suggest that comorbidity of CCA or ACTH-producing adenoma and B-cell lymphoma deserves awareness in our clinical practice, as these two diseases and/or their therapies may interact substantially. CAA should be considered in the major differential diagnosis for an invasive sellar tumor, even without blood ACTH elevation and/or with a history of malignant lymphoma.     

Mania in a girl with Cushing's disease

A 13-year-old girl with Cushing's disease suffered a manic episode. An adenoma of the pituitary gland was found to be the cause. After the adenoma had been removed, the girl's condition returned to normal. The affective disorder was classified as an organic mood disorder (DSM-III-R).     

儿童和青春期垂体腺瘤的诊断和治疗

儿章和青春期垂体腺瘤多数指16或18岁以前经手术证实的病例。全面评估内分泌、影像学改变是诊断的关键、治疗的基础。儿童和青春期PRL腺瘤与成人PRL腺瘤在对溴隐停有效性方面相同。甲介型或气化不良的经窦并不是经蝶手术的禁忌症。关于Cushing’s病的治疗，首选经蝶手术，治愈率可达80％～98％．放射治疗应严格掌握适应症，尽可能减少延迟性的垂体功能低下的发生。术后可以发生各种垂体和下丘脑功能障碍，长期、正规的随访具有特别重要的意义。     

Neural transformation in a pituitary corticotroph adenoma

A pituitary mass was removed by the transsphenoidal approach from a 63-year-old man with the clinical history and laboratory findings characteristic of Cushing's disease with partial hypopituitarism. Histological, immunohistochemical, ultrastructural and immunoelectron microscopic investigation demonstrated a periodic acid-Schiff-positive, adrenocorticotropic hormone (ACTH)-immunoreactive, pituitary corticotroph adenoma with the formation of neural tissue resembling neuropil within the tumor. The neural elements showed immunopositivity for neurofilament protein and ACTH, but were immunonegative for other adenohypophysial hormones and for corticotropin-releasing hormone. Although the molecular mechanism accounting for neural transformation in this corticotroph adenoma remained obscure, based on the clinical, histological and morphological findings it appears that formation of neural tissue most likely indicate a favorable prognosis.     

Intraoperative bilateral cavernous sinus sampling for ACTH measurements during transsphenoidal pituitary surgery in patients with Cushing's disease

Intraoperative bilateral cavernous sinus sampling combined with rapid ACTH measurement was performed in a pilot study in seven patients with Cushing's disease during transsphenoidal pituitary surgery before and immediately after removal of the ACTH-producing pituitary microadenoma. Before tumor removal a gradient in ACTH concentrations greater than 1.5:1 toward the side of the tumor was found in six patients whereas ACTH concentrations in the right and left cavernous sinuses were similar in one patient with a midline tumor. Immediately after tumor removal, six of seven patients showed variable decreases in ACTH levels in the ipsilateral and/or contralateral side, whereas in one patient the ACTH levels in cavernous sinuses failed to reflect successful tumor removal. These results indicate that intraoperative bilateral cavernous sinus sampling combined with rapid ACTH measurement may be useful to confirm and lateralize ACTH-producing pituitary microadenomas during surgery, but ACTH levels measured immediately after tumor removal do not always predict surgical cure.     

病理未能证实垂体腺瘤库欣病的手术疗效(附61例分析)

目的探讨病理结果阴性库欣病的经蝶窦显微外科手术疗效。方法回顾性分析61例病理结果阴性库欣病的临床资料。本组均有典型的皮质醇增多症临床表现;内分泌检查符合库欣病48例,不典型13例;术前MRI诊断为微腺瘤33例,未见异常28例。行经蝶窦入路微腺瘤切除加瘤周垂体组织部分切除31例,垂体前叶部分切除30例。随访1.5～10年,平均3.3年。结果病理为垂体增生31例,其中Crooke细胞呈结节样增生17例;垂体前、后叶组织30例。本组治愈19例(31.2%),缓解16例(26.2%),无效26例(42.6%);有明显皮质醇功能低下表现者17例。术后行垂体放疗8例,肾上腺切除9例。结论病理未能发现肿瘤组织库欣病的疗效低于有明确腺瘤者。垂体放疗或肾上腺切除可以做为手术无效者的二线治疗方法。