A case of non‐functioning pituitary adenoma with Cushing's syndrome upon recurrence

A 49‐year‐old woman presented with left visual disturbance. No signs of Cushing's disease were evident. Basal levels of serum cortisol and plasma adrenocorticotropic hormone (ACTH) were 16.8 μg/dL and 66.0 pg/mL, respectively. MRI demonstrated an irregularly shaped large pituitary tumor, and the patient then underwent transsphenoidal surgery. By light microscopy the tumor represented a chromophobic adenoma with a few of the adenoma cells showing immunoreactivity for ACTH. On the basis of clinical and light microscopic examinations, the diagnosis of silent corticotroph adenoma was made. Electron microscopy, however, demonstrated the honeycomb Golgi complex that has been reported as a typical finding of gonadotroph adenomas. MRI taken 7 months after the first operation revealed adenoma regrowth. Transcranial surgery was performed, and histology demonstrated a chromophobic pituitary adenoma with most cells immunopositive for ACTH. She was treated with gamma knife postoperatively. Three months later, MRI revealed remarkable shrinkage of the adenoma, but she developed typical signs and symptoms of Cushing's disease. Thus, the hormone immunostaining and biological activity of pituitary adenomas may change with time.     

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.     

神经内镜与神经导航辅助显微镜下经鼻蝶入路切除垂体瘤的疗效比较

目的比较神经内镜与神经导航辅助显微镜下经鼻蝶入路切除垂体瘤的临床疗效。 方法选取湖北医药学院附属襄阳市第一人民医院自2016年1月至2018年7月收治的160例垂体瘤患者,用硬币投掷法随机将患者分为神经内镜组（神经内镜下经鼻蝶入路切除垂体瘤）和神经导航组（神经导航辅助显微镜下经鼻蝶入路切除垂体瘤）,每组80例。比较2组患者治疗前后催乳素（PRL）、生长激素（GH）、促肾上腺皮质激素（ACTH）含量,观察2组患者手术指标、临床疗效、并发症的发生情况。 结果神经内镜组手术时间短于神经导航组患者,神经内镜组术中出血量少于神经导航组,神经内镜组术后住院时间短于神经导航组。治疗后比较,神经导航组患者PRL、GH、ACTH含量显著高于神经内镜组。神经内镜组患者有效率（92.50%）高于神经导航组（81.25%）。神经内镜组的尿崩症、视力障碍、鼻腔出血发生率均显著低于神经导航组（P<0.05）。 结论神经内镜相较于神经导航辅助显微镜下经鼻蝶入路切除垂体瘤,临床疗效更佳,并发症少,患者垂体功能恢复情况更好。     

Ghrelin stimulates adrenocorticotrophic hormone (ACTH) secretion by human ACTH-secreting pituitary adenomas in vitro

Ghrelin is a brain-gut peptide with wide-ranging endocrine, metabolic, cardiovascular and neural effects. Ghrelin, like its synthetic counterparts, the growth hormone (GH) secretagogues, has been shown to markedly stimulate adrenocorticotrophic hormone (ACTH) and cortisol secretion in humans and the ACTH-releasing effect of GH secretagogues is even greater in patients with pituitary ACTH-secreting tumours. Furthermore, these tumours synthesize ghrelin itself, suggesting an intrapituitary ghrelin circuit. The aim of the present study was to evaluate the effect of ghrelin on ACTH secretion by human pituitary corticotroph tumours in vitro to test the functionality of this circuit. Nine ACTH-secreting pituitary tumours (four microadenomas, five macroadenomas) were collected during surgery and incubated with 10-100 nM human ghrelin or with 10 nM human corticotrophin-releasing hormone (CRH). Control experiments were performed in rat anterior pituitary primary cultures. ACTH secretion was assessed after 4 h and 24 h incubation by immunometric assay. After 4 h of incubation with ghrelin, medium ACTH concentrations were two- to ten-fold higher compared to ACTH concentrations in unstimulated wells. The ACTH-releasing effect of ghrelin was significantly less than the response elicited by 10 nM CRH (up to 40-fold) Similar results were obtained after 24 h of incubation and a superimposable response pattern was observed in rat anterior pituitary primary cultures. The present study demonstrates that the endogenous GH secretagogue, ghrelin, stimulates ACTH secretion directly from human tumoural corticotrophs, as well as from normal rat pituitary, and indicates that the marked ACTH release elicited by ghrelin in patients with Cushing's disease in vivo is due, at least in part, to its action on the pituitary tumour. However, the reversal of the response pattern reported in vivo, with ghrelin proving a lesser stimulant than CRH in vitro, suggests that additional, suprapituitary mechanisms are involved in the in vivo response. Moreover, these data uphold the concept of a functional intratumoural ghrelin paracrine circuit in human corticotroph adenomas.     

T cell lymphoblastic lymphoma/leukemia within an adrenocorticotropic hormone and thyroid stimulating hormone positive pituitary adenoma: A cytohistological correlation emphasizing importance of intra‐operative squash smear

We present a rare case of primary pituitary T cell lymphoma/leukemia (T‐LBL) in association with adrenocorticotropic hormone (ACTH) and thyroid stimulating hormone (TSH) expressing pituitary adenoma in a 55‐year‐old woman highlighting the importance of intra‐operative squash smears examination. The patient presented with complaints of headache, diminution of vision and recent onset altered sensorium. MRI revealed a mass lesion in the sellar‐suprasellar region with non‐visualization of pituitary gland separately, extending to involve adjacent structures diagnosed as invasive pituitary macroadenoma. Intra‐operative tissue was sent for squash smear examination. The cytology showed a tumor comprising of sheets of immature lymphoid cells intermixed with clusters of pituitary acinar cells with many mitoses and tingible body macrophages. A diagnosis of presence of immature lymphoid cells within the pituitary was offered and differentials of infiltration by lymphoma cells from systemic disease versus primary central nervous lymphoma‐like lymphoma arising in the pituitary adenoma were considered. Later paraffin section examination and immunohistochemistry corroborated with the squash findings and a final diagnosis of primary pituitary T cell lymphoma/leukemia in association with ACTH and TSH expressing pituitary adenoma was made. To date, only six cases of primary pituitary T cell lymphomas, including three T‐LBL cases, have been reported. This is the seventh case and first one additionally describing cytohistological correlation and importance of intra‐operative cytology.     

经鼻蝶手术治疗垂体磁共振扫描阴性的Cushing病

目的 探讨垂体MRI扫描未见异常的Cushing病的诊断和处理原则.方法 回顾性分析16例垂体MRI扫描未见异常的Cushing病患者,表现为血尿皮质醇升高、血皮质醇昼夜节律消失,正常或轻度升高的ACFH;其中大剂量地塞米松抑制试验中被抑制的11例,余5例通过舣侧岩下窦采血(BIPSS)证实垂体性Cushing病;手术采用经单鼻腔蝶窦入路,硬膜切开后发现肿瘤的11例,4例根据BIPSS提示的偏侧,ACTH高的一侧旁正中切开垂体,均发现肿瘤,肿瘤质地较韧,色泽偏黄.1例BIPSS不能提示肿瘤位置,在ACTH高的一侧行半垂体切除.结果 本组的早期缓解率63%(10/16),术后病理证实ACTH腺瘤12例,而增生的4例.结论 对于垂体MRI扫描未见腺瘤,内分泌学检查(包括大剂量地塞米松抑制实验、BLISS)证实垂体性Cushing病,可选择经蝶手术.     

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.     

Cushing's disease in a young woman with anorexia nervosa: pathophysiological implications

This report describes a 17-year old student who was found to have Cushing's syndrome two years after she had developed anorexia nervosa (AN). The Cushing's syndrome was treated with bilateral resection of enlarged, hyperplastic, non-tumorous adrenal glands. The diagnosis was further confirmed four years later when, two to three years after new symptoms had appeared, an ACTH secreting pituitary adenoma (that is, Cushing's disease) was found on surgery. The possible mechanism for the development of Cushing's disease in a patient with prior anorexia nervosa, a sequence of events reported once previously, is discussed. It is suggested that increased hypothalamic-pituitary corticotroph stimulation in association with the anorexia nervosa, a now well-established endocrine phenomenon, activated an occult, inactive pituitary basophil adenoma in this patient, eventually resulting in autonomous pituitary overproduction of ACTH by the tumor.     

Interleukin regulation of prolactin and corticotropin from pituitary adenoma

Recent findings indicate that lymphokines, leukocyte-derived hormones, interact with the hypothalamic-pituitary axis. We examined the role of neurotrophic lymphokines in the neuroendocrine system. Specifically, the action of Interleukin (IL)-1b, IL-2 and IL-6 upon the anterior pituitary hormones, growth hormone (GH), prolactin (PRL) and adrenocoticotropic hormone (ACTH) were studied in rodent pituitary adenoma cell lines. Hormone release by GH and PRL-producing rat adenoma cells (GH3) and ACTH-producing mouse adenoma cells (AtT-20) was analyzed by radioimmunoassay (RIA). Recombinant (r) IL-1beta decreased PRL release from GH3 in a dose-dependent fashion. IL-1 inhibition of PRL production occurred in parallel with IL-1 inhibition of DNA synthesis in GH3 as measured by [(3)H] thymidine incorporation. This result strongly indicates that IL-1 alters PRL production by adenoma cells at the translational level. Low dose IL-2 (10 U/ml) enhanced ACTH production from AtT-20, but higher concentrations of IL-2 failed to affect the release of ACTH. IL-2 did not change the incorporation of [(3)H] thymidine in AtT-20. Previous studies showed that IL-1 and IL-6 induce a significant secretion of ACTH via the hypothalamic-pituitary axis. However, IL-1 and IL-6 failed to affect ACTH secretion by AtT-20. Blood-derived cytokines have direct effects on hormone secretion by pituitary adenoma cells in vitro.     

Responses to corticotrophin-releasing hormone and dexamethasone in a large series of human adrenocorticotrophic hormone-secreting pituitary adenomas in vitro reveal manifold corticotroph tumoural phenotypes

Patients with Cushing's disease are known to present a variable secretory response to stimulatory and inhibitory challenges. Evaluation of the secretory behaviour of pituitary adrenocorticotrophic hormone (ACTH)-secreting adenomas in vitro aids in the comprehension of its behaviour in vivo; however, given the small size of these tumours and the consequent paucity of material available to in vitro studies, a comprehensive study on the secretory behaviour of human corticotroph tumours has not yet been performed. The present study aimed to assess the spectrum of responses to the two main corticotroph modulators, corticotrophin-releasing hormone (CRH) and dexamethasone, in a large series of human ACTH-secreting pituitary tumours. Seventy-two ACTH-secreting pituitary tumours were collected during surgery and established in culture. Specimens were incubated with 10 nm CRH and/or 10 nm dexamethasone for 4 h and 24 h. Secretion in unstimulated, control wells was set at 100% and changes in ACTH concentrations by at least 20% were considered as responses. Parallel experiments in 12 rat anterior pituitary primary cultures were evaluated. A marked ACTH increase was observed during incubation with CRH in 70% of tumoural specimens at 4 h (range 124-3500% of control wells) and in 57% at 24 h (range 122-3323%). Dexamethasone reduced ACTH secretion in almost 50% of tumours (range 78-2% of control at 4 h; 76-3% at 24 h), whereas it did not affect ACTH medium levels in 30% of specimens and induced a paradoxical ACTH increase in 20% of tumours (range 130-327% of control at 4 h; 156-348% at 24 h). By comparison, CRH uniformly increased ACTH levels in rat anterior pituitary primary cultures (mean 745 ± 84% at 4 h; 347 ± 25% at 24 h), whereas dexamethasone decreased ACTH levels by 40-50% in all experiments. In conclusion, the present study of a large series of human ACTH-secreting pituitary tumours in vitro revealed a considerable variability in the responses to CRH and dexamethasone. This finding indicates the existence of multiple corticotroph tumoural phenotypes and may account for the different responses to physiological and pharmacological modulators in vivo.     

Decreased corticotropin-releasing factor receptor expression and adrenocorticotropic hormone responsiveness in anterior pituitary cells of Wistar-Kyoto rats

The Wistar-Kyoto (WKY) rat shows signs of persistent activation of the hypothalamic-pituitary-adrenal axis, but the cause and site of this activation is not yet known. Chronically activated corticotrophs generally show blunted adrenocorticotropic hormone (ACTH) response to corticotropin releasing factor (CRF); therefore, the anterior pituitary responsiveness to ACTH secretagogues, CRF and vasopressin, was compared in male WKY and Wistar rats. Anterior pituitary CRF binding and CRF receptor mRNA expression was significantly decreased in WKY rats. ACTH response to CRF or vasopressin was markedly impaired, and vasopressin failed to potentiate the CRF-stimulated ACTH release in cultured WKY anterior pituitary cells. In contrast, CRF and vasopressin alone and in combination stimulated large, concentration-dependent increases in ACTH release in Wistar anterior pituitary cells. By contrast to the decreased ACTH secretory responses, steady-state anterior pituitary pro-opiomelanocortin mRNA levels were approximately 12-fold greater in WKY rats compared to Wistar rats, and they further increased in response to CRF stimulation. These findings suggest that, although the WKY rat corticotroph is under a chronic state of activation or disinhibition, the in vitro secretory responses to classic ACTH secretagogues are impaired.     

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。     

Difference of lectin binding sites of secretory granules between normal pituitary and adenoma cells

Summary Electron-immunocytochemical staining with lectin (concanavalin A: Con A) binding sites analysis was applied to study secretory granules of human pituitary adenomas and surrounding normal pituitary tissue using post-embedded serial ultrathin sections. Twelve cases of human pituitary adenoma and three specimens of normal pituitary tissue surrounding adenomas were studied: the cases were operated on between 1982 and 1984. The tumors consisted of four prolactin (PRL)-, six growth hormone (GH)-, and two adrenocorticotropic hormone (ACTH)-producing adenomas.In parallel with the detection of Con A binding sites of secretory granules, their secreting hormones were characterized electron-microscopically with the immunocytochemical horseradish peroxidase (HRP) labeling using the avidin-biotin technique. The two cases of ACTH-producing adenomas showed either weak or negative reactions with Con A on secretory granules, while normal ACTH-producing pituitary cells showed strong reactions with Con A on every secretory granule observed. Large secretory granules of PRL- or GH-producing cells showed negative reactions with Con A both in the pituitary adenoma and normal pituitary, while some small granulated or sparsely granulated adenoma cells also showed strong reactions with Con A.The complexity of human pituitary adenomas is illustrated as well as the difference in biochemical structure of normal pituitary cells and pituitary adenoma cells secreting the same specific hormone.     

CURRENT TOPICS IN NEUROPATHOLOGY CUSHING''S DISEASE

The application of modern investigative techniques, particularly electron microscopy and immunohistochemistry, to the pituitary gland in Cushing's disease have confirmed that in the majority of cases (up to 90% in some series) the disease is due to a corticotroph microadenoma. It has also been shown that the tumours may produce not only ACTH, but also other peptides derived from the same precursor molecule, pro-opiomelanocortin and, in a small minority of cases, other pituitary hormones (e.g. prolactin). Since these peptides are known to have physiological actions they may account for some of the varied symptoms and signs of Cushing's disease. Because of the high incidence of single tumours the treatment of choice in many centres has become selective adenomectomy by the transsphenoidal route. However, a minority of cases appear to be the result of primary hypothalamic or central abnormalities and this may account for the identification of a normal pituitary gland or of corticotroph hyperplasia (with or without tumour formation). It is not possible at the present to identify these groups of patients on the basis of biochemical testing. It is hoped that detailed prospective studies correlating hormone secretion, responses to biochemical testing and detailed investigation of pathological tissue will provide further insight into the pathogenesis of particular variants of the disease.     

Silent corticotroph adenomas: presentation of two cases that presented with pituitary apoplexy

Among the group of pituitary adenomas surgically treated, about 25-30% are not associated with clinical or analytical findings of hormonal hypersecretion. The development of immunohistochemical techniques has allowed the demonstration of a subgroup of adenomas that show immunoreactivity against several hormones among the group of, apparently, non-functioning adenomas. This subgroup has been called silent adenomas. Silent adenomas positive for ACTH show a singular clinical picture and different from those adenomas producing Cushing's disease, as they present more frequently as macroadenomas, with more frequent pituitary apoplexy, invasion of cavernous or sphenoidal sinus and recurrences. We present two new cases of silent corticotroph adenomas in two female patients that presented with pituitary apoplexy, one of them after giving birth after a normal full-term pregnancy. Both of them presented with macroadenomas that invaded the sphenoidal and cavernous sinus. Although both tumors were immunoreactive for ACTH, none of the patients presented clinical or analytical findings compatible with Cushing's disease.     

ACTH, cortisol, and corticosterone output after ovine corticotropin-releasing factor challenge during depression and after recovery

Synthetic ovine corticotropin releasing factor (o-CRF) was administered as an intravenous bolus (100 micrograms) to eight patients suffering from a major depressive disorder, endogenous subtype. All patients showed inadequately suppressed cortisol levels after 1 mg dexamethasone. After clinical remission and normalized dexamethasone responses, these patients were reinvestigated with o-CRF stimulation. The mean adrenocorticotropic hormone (ACTH) release from the pituitary corticotroph cells was indiscriminate at both test sessions. Cortisol and corticosterone output after o-CRF tended to be higher during depression than after recovery. The o-CRF-induced increments observed with corticosterone were more marked in comparison with cortisol. Within the limitations of the current protocol, our preliminary data lend support to the view that an increased pituitary ACTH reserve or adrenocortical steroid reserve is not likely to be responsible for the defective pituitary-adrenal regulation in some dexamethasone-resistant depressives.     

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。