Ectopic ACTH-secreting Tumors Research Articles

Ectopic ACTH-secreting tumor of the thymus revealed by a Cushing’s syndrome: case report and review of literature

Tumors of the thymus are rare. Neuroendocrine tumors are extremely rare. We report a case of a 39-year-old man, referred to our hospital for a paraneoplastic Cushing syndrome with a thymic tumor. Despite bilateral adrenalectomy, the patient still had signs of hypercorticism. A CT scan revealed a 25-mm nodule in the thymic compartment. A resection was indicated and surgery was successful. No adjuvant therapy was administrated. After 10 months, the patient was in good health and his clinical symptoms resolved, with no signs of recurrence. Lung and thymic neuroendocrine carcinomas with Cushing syndrome are aggressive with a high risk of recurrence even after a complete resection. A close follow-up is recommended.

CATETERIZAÇÃO DE SEIO PETROSO INFERIOR NO DIAGNÓSTICO DE SÍNDROME DE CUSHING

Introdução: 15% dos casos de síndrome de Cushing ACTH-dependente devem-se a tumor ectópico. Técnicas bioquímicas e radiológicas têm sido desenvolvidas para ajudar na distinção entre produção ectópica ou hipofisária de ACTH. Objetivo: Relato de síndrome de Cushing ACTH-dependente, cuja definição diagnóstica foi realizada por cateterização bilateral de seio petroso inferior. Relato de caso: Mulher, 47 anos, com amenorreia, ganho de peso, fraqueza, hipertensão arterial, osteoporose e transtorno de humor. Ao exame, fácies em lua cheia e giba dorsal, estrias violáceas abdominais de 1,5 cm, membros inferiores com edema. A investigação laboratorial detectou hipercortisolismo ACTH-dependente. Teste de supressão com dexametasona (16 mg) sugeriu produção ectópica de ACTH. Entretanto, exames de imagem não detectaram lesões no sistema nervoso central ou fora dele responsáveis pelo excesso hormonal. A paciente foi encaminhada a outro serviço para realização de cateterização de seio petroso inferior, que não evidenciou gradiente entre os níveis de ACTH dosados próximo à glândula comparados à periferia, confirmando a origem ectópica do ACTH. Novos exames de imagem evidenciaram tumor em timo. Paciente foi submetida à videotoracoscopia com exérese da lesão, recebendo alta no 10º pós operatório com normalização dos níveis de cortisol e ACTH. Conclusão: A cateterização bilateral de seio petroso inferior é o teste que oferece maior sensibilidade e especificidade na diferenciação entre produção hipofisária e ectópica de ACTH. Uma vez que os exames de imagem iniciais não evidenciaram tumor, esse teste foi essencial na confirmação da etiologia ectópica do ACTH, o que motivou nova investigação e, consequente, diagnóstico e tratamento.

Rare case of ectopic ACTH secreting tumour causing cyclical Cushing[apos]s syndrome

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Cushing’s Syndrome due to a non-adrenal ectopic adrenocorticotropin-secreting ewing sarcoma in a child

Ectopic ACTH Syndrome (EAS) is extremely rare in pediatric age group. Sarcomatous tumors causing EAS are even rarer. A nine year and 4 months old male Filipino presented with a 6 months history of gradually enlarging mass on the left distal thigh. He experienced increasing appetite, rapid weight gain of about 27kgs in 5 months, recent onset of widespread acne and darkening of skin around the neck. Physical Examinations revealed cushingoid face, widespread acne, facial hair, phlethora, buffalo hump, truncal obesity, purple abdominal striae and severe acanthosis nigricans on the neck and axilla. Non-inflamed mass and slight tenderness over the left distal thigh were noted. Patient was hypertensive. Weight & height for age were at Z score above 3 and -1, respectively. Body Mass Index at Z score above 2. His pubertal development was classified as Tanner stage 1 testicular and pubic hair development. Work ups revealed hypernatremia, hypokalemia, metabolic alkalosis and elevated levels of serum cortisol and ACTH. Low and high dose dexamethasone suppression tests failed to suppress serum and urine free cortisol levels, findings which were consistent with ectopic ACTH secreting tumor. Radiological findings were normal skull and chest roentgenograms and normal computed tomographic scan of chest and abdomen. Magnetic resonance imaging of Hypothalamo-pituitary was also normal. An Immunohistochemistry result of left distal thigh mass was consistent with Ewing Sarcoma. The patient received chemotherapy with Vincristine, Doxorubicin and Cyclophosphamide. Unfortunately, patient succumbed to death 5 days post chemotherapy due to severe sepsis.

Tumor Localization in Ectopic Cushing Syndrome Using Combined PET/CT Imaging

Diagnosis of ectopic Cushing syndrome is challenging. The best imaging approach for localizing ectopic ACTH-secreting tumors is not defined. Here, we report on a 68-year-old woman with new-onset hypertension (>200/90 mm Hg) who was referred to our institution with suspicion of ectopic ACTH-secreting tumor for further work-up. Combined FDG PET/CT as a whole-body imaging modality revealed a neuroendocrine tumor of the pancreatic tail confirmed by surgical exploration.

The prevalence and relevance of adrenal masses in patients with sporadic gastroenteropancreatic neuroendocrine tumours (GEP‐NET)

The widespread application of abdominal computerized tomography (CT) imaging has revealed that 0.98-4.0% of individuals harbour adrenal lesions (incidentalomas). There is, however, paucity of information regarding the prevalence of adrenal lesions in patients with gastroenteropancreatic neuroendocrine tumours (GEP-NETS). Purpose of this study was to estimate the prevalence of adrenal lesions in patients with GEP-NETS and identify their radiological features and clinical significance. The prevalence of adrenal lesions was estimated retrospectively in 438 patients with GEP-NETS who underwent abdominal imaging. Secretory status and changes in size were documented during subsequent follow-up. MEN-1 patients and ectopic ACTH-secreting tumours were excluded. Adrenal lesions were detected in 32 (8.4%) of 383 patients included. The majority (22 patients - 69%) were located at the left adrenal gland and the mean size was 23.6 mm. In two patients, one with a well and another with a poorly differentiated tumour, clinicopathological features suggested adrenal metastases. During a mean follow-up period of 69.5 months, no subsequent growth of any adrenal lesion was observed. Endocrine evaluation documented subclinical glucocorticoid hypersecretion in 4 cases (14%). The presence of adrenal lesions did not correlate to distant metastases, however, they were observed more frequently in patients with G3 tumours. The prevalence of adrenal lesions in patients with GEP-NETs was found to be higher than the general population and mostly represent benign adrenal adenomas (except patients with G3 tumours). Nevertheless, individualized assessment of imaging characteristics should be still considered.

A Case of Multiple Endocrine Neoplasia 2B with Probable Ectopic Adrenocorticotropic Hormone-Secreting Liver Metastasis from Medullary Thyroid Carcinoma

A 31 year old woman was diagnosed with multiple endocrine neoplasia (MEN) 2B at 10 years old. Dark pigmentation gradually developed on her skin and her serum adrenocorticotropic hormone (ACTH) was high, suggesting concurrent ectopic ACTH syndrome (EAS). Corticotropin-releasing hormone (CRH) loading test ruled out Cushing's disease and supported the diagnosis of EAS. Multiple low attenuation mass in the liver was observed in a computed tomography (CT) scan, and was suspected as ectopic ACTH-secreting metastatic tumor from medullary thyroid carcinoma (MTC). ACTH production by MTC is relatively rare, particularly in patients with MEN; patients with ectopic ACTH-secreting liver metastatic tumor from MTC in MEN 2B have never been reported previously.

Cabergoline monotherapy in the long-term treatment of Cushing's disease

Cabergoline is a long-acting dopamine receptor agonist used to treat prolactinomas. Identification of D(2) receptors in corticotroph tumors led to clinical trials of cabergoline therapy in limited cases of Nelson's syndrome, ectopic ACTH-secreting tumors, and recently Cushing's disease (CD). To evaluate the long-term efficacy of cabergoline monotherapy in patients with CD. Retrospective analysis of non-randomized clinical therapy with cabergoline in 30 patients with CD treated in academic centers of Buenos Aires and Montreal. Cabergoline was initiated at 0.5-1.0 mg/week and adjusted up to a maximal dose of 6 mg/week based on urinary free cortisol (UFC) levels. Complete response to cabergoline was defined as a sustained normalization of UFC with at least two normal values measured at 1-3 months interval; partial response was defined as a decrease of UFC to <125% of the upper limit of normal, and treatment failure as UFC ≥ 125% of it. Within 3-6 months, complete response was achieved in 11 patients (36.6%) and partial response in 4 patients (13.3%). After long-term therapy, nine patients (30%) remain with a complete response after a mean of 37 months (range from 12 to 60 months) with a mean dose of 2.1 mg/week of cabergoline. Two patients escaped after 2 and 5 years of complete response, but one patient transiently renormalized UFC after an increase in cabergoline dosage. No long-term response was maintained in four initial partial responders. Cabergoline monotherapy can provide an effective long-term medical therapy for selected patients with CD, but requires close follow-up for dose adjustments.

Utility of Various Functional and Anatomic Imaging Modalities for Detection of Ectopic Adrenocorticotropin-Secreting Tumors

Because ectopic ACTH-secreting (EAS) tumors are often occult, improved imaging is needed. Our objective was to evaluate the utility of [(111)In-DTPA-d-Phe]pentetreotide scintigraphy [octreotide (OCT)] imaging at 6 mCi [low OCT (LOCT)] and 18 mCi [high OCT (HOCT)], [(18)F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) and [(18)F]l-3,4-dihydroxyphenylalanine (F-DOPA)-PET scans, computed tomography (CT), and magnetic resonance imaging (MRI). The study was a prospective evaluation at a clinical research center. Forty-one subjects participated, 30 (17 female) with resected EAS tumors and 11 (three female) with occult EAS, based on inferior petrosal sinus sampling results and imaging studies. INTERVENTION included CT and MRI of neck, chest, abdomen, LOCT (with or without HOCT) and FDG- or F-DOPA-PET without CT every 6-12 months. Tumor identification was the main outcome measure. Most recent results were analyzed. Eighteen patients had tumor resected on the first visit; otherwise, surgery occurred 33 +/- 25 (9-99) months later. Tumor size was 1.9 +/- 1.7 (0.8-8.0) cm; 83% were intrathoracic. CT, MRI, LOCT, HOCT, FDG-PET, and F-DOPA-PET had sensitivities per patient of 93% [95% confidence interval (CI) = 79-98%], 90% (95% CI = 74-96%), 57% (95% CI = 39-73%), 50% (95% CI = 25-75%), 64% (95% CI = 35-85%), and 55% (95% CI = 28-79%) and positive predictive values (PPV) per lesion of 66, 74, 79, 89, 53, and 100%, respectively. LOCT and PET detected only lesions seen by CT/MRI; abnormal LOCT or F-DOPA-PET improved PPV of CT/MRI. By modality, the fraction of patients with one or more false-positive findings was 50% by CT, 31% by MRI, 18% by L/HOCT, and 18% by FDG-PET. Eight occult EAS patients had 64 +/- 58 (9-198) months follow-up; others had none. High sensitivity and PPV suggest thoracic CT/MRI plus LOCT scans for initial imaging, with lesion confirmation by two modalities.

Utility of [18F] fluoro-2-deoxy-d-glucose positron emission tomography in the localization of ectopic ACTH-secreting tumors

Ectopically ACTH producing tumors may be difficult to localize by conventional radiology and functional imaging may be helpful. Case 1: 31-year-old man was diagnosed with ectopic ACTH-dependent Cushing's syndrome (ECS). Thorax CT revealed a 1.3 cm nodular opacity in upper left lobe, suggestive of residual lesion. [(18)F] fluoro-2-deoxy-D: -glucose ([(18)F] FDG) positron emission tomography ([(18)F] FDG PET) scan revealed mild glycolytic metabolic activity. Pathological examination confirmed an ACTH-positive carcinoid tumor. Case 2: 53-year-old woman presented with very rapid onset ECS. Pituitary MRI was normal. Thorax CT revealed no tumoral lesion. Abdominal and pelvic MRI showed images suggestive of hepatic and iliac, femoral and lumbar secondary implants. [(18)F] FDG PET scan revealed intense uptake in uterus, especially cervix, suggesting this to be the primary tumor site. These cases illustrate the role of [(18)F] FDG PET in the investigation of an ECS where conventional imaging studies were not elucidative in the search for a responsible tumor.

The role of bilateral inferior petrosal sinus sampling in the diagnosis of Cushing's syndrome

Adrenocorticotropin hormone (ACTH)-dependent Cushing's syndrome is most often due to a pituitary corticotroph adenoma, with ectopic ACTH-secreting tumors representing approximately 15% of cases. Biochemical and radiological techniques have been established to help distinguish between these two entities, and thus aid in the localization of the neoplastic lesion for surgical resection. The test that offers the highest sensitivity and specificity is bilateral inferior petrosal sinus sampling (BIPSS). BIPSS is an interventional radiology procedure in which ACTH levels obtained from venous drainage very near the pituitary gland are compared to peripheral blood levels before and after corticotropin hormone (CRH) stimulation. A gradient between these two locations indicates pituitary Cushing's, whereas the absence of a gradient suggests ectopic Cushing's. Accurate BIPSS results require hypercortisolemia to suppress normal corticotroph ACTH production and hypercortisolemia at the time of the BIPSS to assure excessive ACTH secretion. In some cases, intrapituitary gradients from side-to-side can be helpful to localize small corticotroph adenomas within the sella. BIPSS has rare complications and is considered safe when performed at centers with experience in this specialized technique.

A Dural Tale

A 44-yr-old cushingoid-appearing male was referred to the Massachusetts General Hospital for evaluation of a new sellar mass. He presented with rapid onset of symptoms over 6 months, including weight loss and hypokalemia. The 3-cm T1-enhancing sellar mass tapered posteriorly along the left tentorium, forming a “dural tail” (Fig. 1), suggesting a meningioma. Endocrine evaluation revealed ACTH-dependent Cushing’s syndrome, with a urine-free cortisol of 303 g/24 h (normal 20–70 g/24 h) and an ACTH level of 83 pg/ml (normal 6–76 pg/ml). An inferior sinus petrosal catheterization, performed due to the unusual radiological characteristics of the sellar mass and symptoms of weight loss and hypokalemia, confirmed a central source of excess ACTH secretion. Tissue obtained during transsphenoidal debulking revealed a corticotroph macroadenoma without evidence of meningioma. The dural tail sign is usually associated with meningiomas (1–3). The sign was thought initially to be specific for meningioma but has been described in association with other pituitary and intracranial processes. The sensitivity and specificity of the dural tail sign are approximately 60 and 95%, respectively (4). The tail results from a reactive inflammatory process in the dura mater adjacent to the point of tumor attachment rather than direct tumor infiltration. This case demonstrates that the dural tail sign may be seen with pituitary macroadenomas, and such tumors should be included in the differential diagnosis associated with this sign. The tumor in this case is unusual for Cushing’s disease in its size and radiological presentation (5). This case also demonstrates that ACTH-secreting macroadenomas can be associated with severe symptoms of cortisol excess and mimic ectopic ACTH-secreting tumors.

Primary hepatic carcinoid tumor presenting as Cushing’s syndrome

Hepatic carcinoid tumors are very uncommon; most are clinically non-functional and very few present with the symptoms of carcinoid syndrome. ACTH-producing carcinoid tumors most commonly originate in the lung or thymus and present insidiously with bronchospasm and/or chest mass. Occasionally, ectopic ACTH syndromes have been reported in association with pancreatic islet cell tumors, medullary thyroid cancer, pheochromocytoma, small-cell lung carcinoma, and rarely, ovarian and prostate tumors. We report here a patient with an ectopic ACTH-secreting primary hepatic carcinoid tumor who presented with cushingoid appearance, profound proximal muscle weakness, severe lower extremity edema, and markedly elevated urinary free cortisol. ACTH levels were in the low normal range. A solitary vascular hepatic lesion was found on magnetic resonance imaging, which was isodense with the surrounding liver on octreotide scan and photopenic on an 18-fluorodeoxyglucose (18FDG)-positron emission tomography (PET) scan. Following surgical resection of the hepatic tumor, histopathology confirmed an ACTH-secreting neuroendocrine tumor (NET), the patient had complete resolution of hypercortisolemic symptoms and remains in remission, now 4 yr after hepatic tumor resection. This case reports the first ACTH-secreting primary hepatic NET presenting as ectopic Cushing's syndrome. Interesting aspects of this case include the presence of a pituitary incidentaloma, the low normal ACTH, and photopenia on 18FDG-PET imaging.

Ectopic Cushing' syndrome caused by a neuroendocrine carcinoma of the mesentery

BackgroundACTH overproduction within the pituitary gland or ectopically leads to hypercortisolism. Here, we report the first case of Cushing' syndrome caused by an ectopic ACTH-secreting neuroendocrine carcinoma of the mesentery. Moreover, diagnostic procedures and pitfalls associated with ectopic ACTH-secreting tumors are demonstrated and discussed.Case presentationA 41 year-old man presented with clinical features and biochemical tests suggestive of ectopic Cushing's syndrome. First, subtotal thyroidectomy was performed without remission of hypercortisolism, because an octreotide scan showed increased activity in the left thyroid gland and an ultrasound revealed nodules in both thyroid lobes one of which was autonomous. In addition, the patient had a 3 mm hypoenhancing lesion of the neurohypophysis and a 1 cm large adrenal tumor. Surgical removal of the pituitary lesion within the posterior lobe did not improve hypercortisolism and we continued to treat the patient with metyrapone to block cortisol production. At 18-months follow-up from initial presentation, we detected an ACTH-producing neuroendocrine carcinoma of the mesentery by using a combination of octreotide scan, computed tomography scan, and positron emission tomography. Intraoperatively, use of a gamma probe after administration of radiolabeled 111In-pentetreotide helped identify the mesenteric neuroendocrine tumor. After removal of this carcinoma, the patient improved clinically. Laboratory testing confirmed remission of hypercortisolism. An octreotide scan 7 months after surgery showed normal results.ConclusionThis case underscores the diagnostic challenge in identifying an ectopic ACTH-producing tumor and the pluripotency of cells, in this case of mesenteric cells that can start producing and secreting ACTH. It thereby helps elucidate the pathogenesis of neuroendocrine tumors. This case also suggests that patients with ectopic Cushing's syndrome and an octreotide scan positive in atypical locations may benefit from explorative radioguided surgery using 111In-pentetreotide and a gamma probe.

Reduction of a Pancreatic Tumor after Total Removal of an ACTH Secreting Pituitary Tumor: Differential Diagnosis of Cushing's Syndrome

Endocrinologic tests sometimes fail to distinguish adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma from ectopic ACTH-secreting tumor. The authors experienced a case of Cushing's disease associated with a pancreatic tumor. Venous sampling contributed to the final diagnosis of Cushing's disease in this complex case, while endocrinologic tests showed paradoxical results. A 54-year-old woman presented with Cushing's syndrome and pancreatic tumor. Magnetic resonance imaging (MRI) failed to reveal a pituitary tumor, but a gadolinium-enhanced tumor with cystic components was seen in the pancreatic tail. Results of conventional endocrinologic tests suggested ectopic ACTH syndrome, but venous sampling including cavernous sinus sampling indicated an ACTH-secreting pituitary adenoma. Transsphenoidal surgery revealed a pituitary microadenoma, and total removal of the tumor was achieved. Postoperative abdominal MRI revealed that the pancreatic tumor diminished gradually without treatment. Selective cavernous sinus sampling was useful for distinguishing ACTH-secreting pituitary adenoma from ectopic ACTH syndrome in this complex case. This was a rare case in which the pancreatic tumor diminished after total removal of the ACTH-secreting pituitary adenoma.

Ghrelin, Hypothalamus-Pituitary-Adrenal (HPA) Axis and Cushing's Syndrome

Ghrelin, a peptide predominantly produced by the stomach, has been discovered as a natural ligand of the GH Secretagogue receptor type 1a (GHS-R1a), known as specific for synthetic GHS. Ghrelin has recently attracted considerable interest as a new orexigenic factor. However, ghrelin exerts pleiotropic actions that are explained by the widespread distribution of ghrelin and GHS-R expression. Besides strong stimulation of GH secretion, the neuroendocrine ghrelin actions also include significant stimulation of both lactotroph and corticotroph secretion; all these actions depend on acylation of ghrelin in serine-3 that allows binding and activation of the GHS-R1a. However, GHS-R subtypes are likely to exist; they also bind unacylated ghrelin that is, in fact, the most abundant circulating form and exerts some biological actions. Ghrelin secretion is mainly regulated by metabolic signals, namely inhibited by feeding, glucose and insulin while stimulated by energy restriction. The role of glucocorticoids on ghrelin synthesis and secretion is still unclear although morning ghrelin levels have been found reduced in some patients with Cushing's syndrome; this, however, would simply reflect its negative association to body mass. Ghrelin, like synthetic GHS, stimulates ACTH and cortisol secretion in normal subjects and this effect is generally sensitive to the negative glucocorticoid feedback. It is remarkable that, despite hypercortisolism, ghrelin as well as synthetic GHS display marked increase in their stimulatory effect on ACTH and cortisol secretion in patients with Cushing's disease. This is even more intriguing considering that the GH response to ghrelin and GHS is markedly reduced by glucocorticoid excess. It has been demonstrated that the ACTH-releasing effect of ghrelin and GHS is purely mediated at the central level in physiological conditions; its enhancement in the presence of ACTH-secreting tumours is, instead, likely to reflect direct action on GHS receptors present on the neoplastic tissues. In fact, peculiar ACTH hyperresponsiveness to ghrelin and GHS has been observed also in ectopic ACTH-secreting tumours.

High cardiovascular risk in patients with Cushing's syndrome according to 1999 WHO/ISH guidelines

In patients with Cushing's syndrome (CS) cardiovascular complications determine a mortality rate four times higher than in an age- and gender-matched population. Therefore, we calculated the global cardiovascular risk in patients with CS. We applied the World Health Organization--International Society of Hypertension (WHO/ISH) 1999 guidelines for the estimation of cardiovascular risk in 38 females and 11 males with CS; 27 pituitary adenomas, 15 adrenal adenomas, four adrenal carcinomas and three ectopic ACTH-secreting tumours. The risk of major cardiovascular events was estimated considering the combined effect of several risk factors (hypertension, diabetes, etc.), organ damage (left ventricular hypertrophy (LVH), proteinuria, etc.) and associated pathologies. Four categories of absolute cardiovascular disease risk were defined (low, medium, high, very high). Eighty per cent of patients presented a 'high' or 'very high' cardiovascular risk; 85.1% of the patients were hypertensive with a mild-moderate hypertension (68%). Forty-seven per cent of patients were diabetics and 41.3% were obese. Hyperlipidaemia was less frequent (37.5%). Fasting glycaemia was the only cardiovascular risk factor that correlated with a degree of hypercortisolism. Duration of disease correlated with the presence of obesity (P < 0.0008) and hypertension (P < 0.03) but not with the presence of diabetes or dyslipidaemia and seemed to be the only significant predictor of cardiovascular risk (P = 0.03). Patients with active CS present a remarkably increased cardiovascular risk. Considering that the biochemical cure of hypercortisolism is often difficult to obtain, especially in Cushing's disease, and that cardiovascular risk could persist even after the 'cure', control of risk factors should be one of the primary goals of the therapy.

New Perspectives in the Treatment of Cushing's Syndrome

Regardless of etiology, all cases of endogenous Cushing's syndrome are due to increased production of cortisol by the adrenal gland. Most are caused by adrenocorticotrophic hormone (ACTH)-secreting pituitary adenomas. Alternatively, the glucocorticoid excess may be due to adrenal neoplasia or to ectopic ACTH-secreting tumors. Cushing's syndrome is characterized by endocrine and metabolic alterations such as truncal obesity, hypertension, weakness, amenorrhea, hyperglycemia, osteoporosis and depression. Unless treated, the disease is associated with high morbidity, and ultimately, mortality. Depending on the etiology of Cushing's syndrome two different treatment modalities are possible: reduction of pituitary ACTH production or reduction of adrenocortical cortisol secretion. In the absence of efficient drug therapy, transsphenoidal resection of the pituitary adenoma is the primary treatment of choice for the reduction of ACTH secretion. In the last years there was much progress in understanding the molecular mechanisms that control the function of the hypothalamic-pituitary-adrenal axis. Thus, new insights made it possible to identify potential drug targets for the treatment of Cushing's syndrome. The present article reviews different drug targets and therapeutic options including drugs that control the central ACTH regulation, e.g. by modulating signaling pathways and transcriptional regulation of ACTH biosynthesis, corticotrophin releasing hormone (CRH) or glucocorticoid receptor antagonists, inhibitors of glucocorticoid synthesis, ketoconazole, somatostatin and dopamine analogs. Some of these substances might be useful for the treatment of Cushing's syndrome.

Cyclical Cushing Syndrome Caused by Intermittent Ectopic ACTH Homogenesis Responsive to Somatostatin Analogues

Abstract: Cushing disease accounts for 80% to 85% of ACTH-dependent disease, whereas 15% to 20% is caused by ectopic sources. Cyclical Cushing syndrome is an unusual phenomenon and is frequently associated with a pituitary adenoma. Diagnostic and therapeutic problems arise when diagnostic tests are performed in the “quiescent phase” of the disease at a time when cortisol levels are normal, when the tests confirm a cyclic ectopic hypercortisolemic pattern but no tumor can be identified, or when radiologic evaluation reveals a coincidental pituitary abnormality. We present the case of a 29-year-old female with clinical Cushing syndrome caused by periodic hormonogenesis from an ectopic ACTH-secreting tumor, which was proved to be a bronchial carcinoid that responded to long acting somatostatin analogue (SM-a) treatment (Sandostatin LAR). The patient also had a coexisting pituitary microadenoma. Recently, the SM-a octreotide has been shown to be effective in reducing cortisol levels in several communications. Our case confirms previous data concerning the usefulness of this therapeutic regime in reducing cortisol and ACTH levels in patients with ectopic ACTH hormonogenesis. Moreover, to our knowledge this is the first report that shows such a beneficial effect using the new long acting SM-a (Sandostatin LAR).

Cavernous sinus sampling

I NTERVENTIONAL neuroradiology now plays a role in the diagnosis of Cushings disease. The disease is characterized by an increased production of corticosteroids, leading to the classic features: increase in central body weight with sparing of the extremities, increased body hair, pliable skin, hypertension, and hyperglycemia. The release of corticosteroids from the adrenal gland is controlled by a negative feedback mechanism. Corticotropin is released from the hypothalamus and travels to the anterior pituitary gland via a portal venous system. Corticotropin stimulates the release of adrenocorticotrophic hormone (ACTH) from the anterior pituitary gland. This hormone stimulates the production and secretion of corticosteroids from the adrenal cortex. The increase of corticosteroid levels in the blood has a negative feedback effect on further release of corticotropin from the hypothalamus. An excess of corticosteroids may thus be caused by an ACTH-secreting pituitary adenoma or an adrenal cortex adenoma, or an ectopic ACTHsecreting tumor. Usually, magnetic resonance imaging scans of the brain will show an enlarged pituitary gland if the location of the tumor is in the anterior pituitary gland. However, in some patients the precise location of the adenoma is unclear. It is thus necessary to stimulate secretion of the pituitary gland by corticorelin and sample cavernous sinus and peripheral venous blood samples for levels of the ACTH. 1'2 The procedure is fairly simple. Using biplane angiography, bilateral femoral venous catheters are inserted. The microcatheters are advanced bilaterally into each cavernous sinus. Baseline blood samples from the periphery and cavernous sinus are sent as indicated in Fig 1. Corticorelin is then injected intravenously, and samples of blood are taken bilaterally from each of the areas as indicated at intervals of 5, 10, 15, and 20 minutes (Fig 2). The anesthesia considerations for this procedure are dictated by the pathophysiology of Cushing's disease. These patients are often hypertensive and have elevated serum glucose levels. Care must be taken in positioning the patient and protecting their extremities because they have such fragile tissues. Their obesity may make airway management, intubation, and securing intravenous access very difficult. The procedure may be done under local or general anesthesia. Our interventional neuroradiologist usually prefers general anesthesia for these cases unless there are good reasons to do this with intravenous sedation plus local anesthesia. The procedure is done on an out-patient basis, and there should be minimal post-procedure pain or complications.