Unusual Cause of Ectopic Secretion of Adrenocorticotropic Hormone: Cushing Syndrome Attributable to Small Cell Prostate Cancer

ObjectiveTo report a rare cause of ectopic adrenocorticotropic hormone (ACTH) secretion leading to severe Cushing syndrome.MethodsWe describe the clinical presentation and management of a case of Cushing syndrome attributable to ectopic ACTH secretion from small cell cancer of the prostate.ResultsIn a 70-year-old man with hypertension and diabetes, congestive heart failure developed. He was found to have severe hypokalemia (serum potassium, 1.7 mEq/L) and a huge pelvic mass on a computed tomographic scan performed because of a complaint of urinary retention. Transurethral biopsy of the prostate showed features of small cell prostate cancer. Hormonal evaluation revealed a high urine free cortisol excretion of 6,214.5 μg/d (reference range, 36 to 137), confirming the diagnosis of Cushing syndrome. A serum ACTH level was elevated at 316 ng/dL (reference range, 10 to 52). An overnight highdose (8 mg orally) dexamethasone suppression test was positive (serum cortisol levels were 43.2 and 41 μg/dL before and after suppression, respectively), and magnetic resonance imaging of the pituitary gland disclosed no abnormalities. A prostate biopsy specimen showed small cell prostate cancer with positive staining for ACTH. The tumor was found to be unresectable, and the poor condition of the patient did not allow for bilateral adrenalectomy. He was treated with ketoconazole and metyrapone, which yielded good temporary control of his Cushing syndrome (24-hour urine free cortisol decreased to 55.2 μg/d). He received 1 cycle of chemotherapy (etoposide and cisplatin), but he died 6 months later as a result of sepsis.ConclusionSmall cell prostate cancer is a rare subtype that can be associated with ectopic secretion of ACTH and severe Cushing syndrome. With this subtype of prostate cancer, Cushing syndrome should be considered and appropriately managed. (Endocr Pract. 2010;16:249-254)     

Pituitary Mri Findings in Patients With Pituitary and Ectopic Acth-Dependent Cushing Syndrome: Does A 6-Mm Pituitary Tumor Size Cut-Off Value Exclude Ectopic Acth Syndrome?

Objective: Expert opinion and a consensus statement on Cushing syndrome (CS) indicate that in a patient with a clinical presentation and biochemical studies consistent with a pituitary etiology, the presence of a pituitary tumor ≥6 mm is highly suggestive of Cushing disease (CD). The purpose of the present study was to determine the optimal pituitary tumor size that can differentiate between patients with CD and ectopic adrenocorticotrophic hormone (ACTH) secretion (EAS) and obviate the need for inferior petrosal sinus sampling (IPSS).Methods: We performed a retrospective study of 130 patients seen between 2000 and 2012 including 104 patients with CD and 26 patients with EAS.Results: A pituitary lesion was reported in 6/26 (23%) patients with EAS and 71/104 (68.3%) patients with CD, with median (range) sizes of 5 mm (3–14) and 8 mm (2–31), respectively. All tumors in the EAS group measured ≤6 mm except for 1 that measured 14 mm. The presence of a pituitary tumor >6 mm in size had 40% sensitivity and 96% specificity for the diagnosis of CD. ACTH levels >209 pg/mL and serum potassium <2.7 mmol/L were found in patients with EAS. All patients with EAS had a 24-hour urine free cortisol (UFC) >3.4 times the upper limit of normal (×ULN)Conclusion: Pituitary incidentalomas as large as 14 mm in size can be seen in patients with EAS. However, the 6-mm tumor size cut-off value provided 96% specificity and may be a reasonable threshold to proceed with surgery without the need for IPSS when the biochemical data support a pituitary etiology.Abbreviations: ACTH = adrenocorticotropic hormone CD = Cushing disease CRH = corticotropin-releasing hormone CS = Cushing syndrome EAS = ectopic ACTH secretion IPSS = inferior petrosal sinus sampling HDDST = high-dose dexamethasone suppression test LDDST = low-dose dexamethasone suppression test MRI = magnetic resonance imaging UFC = urine free cortisol ULN = upper limit of normal     

Cushing Disease Revealed by Bilateral Atypical Central Serous Chorioretinopathy: Case Report

ObjectiveWe report the case of a patient with Cushing disease revealed by bilateral central serous chorioretinopathy (CSCR).MethodsWe present the clinical history, physical findings, laboratory results, and imaging studies of a 53-year- old Chinese woman with a Cushing disease revealed by bilateral CSCR. The association with CSCR and the pertinent literature are reviewed.MethodsWe present the clinical history, physical findings, laboratory results, and imaging studies of a 53-year- old Chinese woman with a Cushing disease revealed by bilateral CSCR. The association with CSCR and the pertinent literature are reviewed.ResultsA 53-year-old patient initially presented to the Department of Ophthalmology with a 4-week history of decreased vision in the left eye. Standard ophthalmologic examination and fluorescein angiography established the diagnosis of bilateral CSCR. Systemic clinical signs and biochemical analysis indicated hypercortisolism. Magnetic resonance imaging (MRI) of the pituitary gland showed a left-side lesion compatible with a microadenoma. The diagnosis of Adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome secondary to a pituitary microadenoma was selected. Endoscopic endonasal transsphenoidal surgery was performed and the pituitary adenoma was successfully removed. The histology confirmed the presence of ACTH-immunopositive pituitary adenoma. Early postoperative morning cortisol levels indicated early remission. At 6 weeks postoperatively, the patient’s morning cortisol remains undetectable, and serous retinal detachments had regressed.ConclusionCSCR is an uncommon manifestation of endogenous Cushing syndrome. It can be the first presentation of hypercortisolism caused by Cushing disease. CSCR should be considered when assessing patients with Cushing syndrome complaining of visual disorders. On the other hand, it is useful in patients with an atypical form of CSCR to exclude Cushing’s syndrome. (Endoer. Praet. 2013;19:el29-el33)     

Venous Sampling for Cushing Disease: Comparison of Internal Jugular Vein and Inferior Petrosal Sinus Sampling

Objective: Because magnetic resonance imaging (MRI) fails to detect many adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas, inferior petrosal sinus sampling (IPSS) is considered the gold standard to differentiate Cushing disease (CD) from ectopic ACTH secretion syndrome (EAS). Some authors have suggested internal jugular vein sampling (IJVS) as an alternative to IPSS.Methods: We simultaneously compared IJVS to IPSS in 30 consecutive patients referred for ACTH-dependent Cushing syndrome and equivocal MRI exams. Five sites were simultaneously sampled in each patient (right and left IPS, right and left IJV, and femoral vein) before and after the administration of corticotrophin-releasing hormone or desmopressin. The test was considered consistent with CD when the IPS to peripheral ratio was >2 at baseline or >3 after stimulus and the IJV to peripheral ratio was >1.7 at baseline or >2 after stimulus.Results: In 27 of 30 patients, IPSS results were consistent with a central source of ACTH. Two of the other 3 patients had EAS (one lung carcinoid and one occult), and 1 patient had pathology-proven CD. The sensitivity of IPSS was 96.4%. Only 64.2% of these patients had results meeting criteria for a central source of ACTH by IJVS criteria. Twenty patients with centralizing IPPS have undergone pituitary surgery. Of these, the central origin of excessive ACTH was confirmed with certainty in 16 patients. Among these 16 patients, the IPSS sensitivity was 93.8%, whereas 5 patients had false-negative IJVS (68.7% sensitivity).Conclusion: These results do not support the routine use of IJVS in establishing if the pituitary is the source of excessive ACTH.Abbreviations:ACTH = adrenocorticotropic hormoneCD = Cushing diseaseCRH = corticotrophin-releasing hormoneCS = Cushing syndromeDDAVP = desmopressinEAS = ectopic ACTH secretionIJVS = internal jugular vein samplingIPSS = inferior petrosal sinus samplingJVS = jugular venous samplingMRI = magnetic resonance imaging     

Cushing's Syndrome Due to Ectopic Adrenocorticotrophic Hormone Production by Olfactory Neuroblastoma

ObjectiveTo review a case of olfactory neuroblastoma (ON) with Cushing’s syndrome (CS) due to ectopic production of adrenocorticotrophic hormone (ACTH) and compare the histopathologic diagnosis, treatment modality, and prognostic factors with the literature.MethodsWe report the clinical presentation, biochemistry, imaging, histopathology, treatment, and outcome of a patient with ON. We conducted an English language literature review of CS due to ectopic ACTH production and ON.ResultsCS due to ectopic ACTH production is uncommon, and CS due to ON is extremely rare. A 19-year-old Hispanic man presented with right nasal obstruction, involuntary weight gain, and intensely pruritic skin rash. Examination revealed large, wide purple striae on both arms and the abdomen. Head magnetic resonance imaging (MRI) revealed a right ethmoid sinus enhancing mass extending into the orbit, nasal cavity, and maxillary and sphenoid sinuses. Laboratory results showed a pm cortisol level of 26 mcg/dL, a 24-hour urinary free cortisol level of 7,507 mcg, an ACTH level of 83 pg/mL, and nonsuppression of cortisol with an overnight dexamethasone suppression test (1 and 8 mg). A biopsy revealed ON, and immunohistochemistry (IHC) was positive for ACTH. He underwent chemotherapy followed by surgical debulking and adjuvant radiation therapy, with no disease recurrence through the last follow-up in February 2012. Plasma and urinary cortisol levels normalized following surgery.ConclusionThis is the first case reported of a Hispanic male with an uncommon tumor (ON) and an even more uncommon presentation, ectopic ACTH production causing CS. The extremely high ACTH levels and plasma and urine cortisol levels dramatically dropped following multimodality management. So far, he has had 2.5 years of disease-free survival. (Endocr Pract. 2014;20:e47-e52)     

Clinical Heterogeneity of Ectopic ACTH Syndrome: A Long-Term Follow-Up Study

Objective: Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a heterogeneous condition caused by neuroendocrine neoplasms (NENs) located in the lungs, thymus, or pancreas. Our purpose was to evaluate the long-term outcome of these patients.Methods: Retrospective study at a referral center. The charts of 164 patients with Cushing syndrome, followed at our center from 1993 to 2019, were analyzed.Results: EAS was found in 16 patients (9.75%, 9 women, mean age 36.01 years) who had been followed for a median of 72 months. The source of EAS was a NEN in 10 patients (8 bronchial and 2 thymic carcinoid tumors) and a mixed corticomedullary tumor, consisting of a pheochromocytoma and an adrenocortical carcinoma in 1 patient. In 2 of the 6 patients initially considered to have occult EAS, the source of the ACTH excess became apparent after adrenalectomy, whereas in the remaining 4 (25%) patients, it has remained occult. Of the 11 patients in whom resection of the NEN was attempted, 10 patients achieved an early remission (91%), but 4 (25%) of these patients had a recurrence during follow-up (biochemically and clinically silent in 2 patients). Three patients died (18.75%): the young woman with the mixed corticomedullary tumor, a man with a thymic NEN that evolved into a neuroendocrine (NE) carcinoma after 11 years of follow-up, and a woman with a bronchial NEN.Conclusion:The course of EAS varies according to tumor type and grade. Some patients have a protracted course, whereas others may evolve into neuroendocrine carcinomas.Abbreviations: ACTH = adrenocorticotropic hormone; CS = Cushing syndrome; CT = computed tomography; CV = coefficient of variation; EAS = ectopic ACTH syndrome; IQR = interquartile range; NEN = neuroendocrine neoplasm; SCCL = small cell carcinoma of the lung; TSS = transsphenoidal surgery; UFC = urinary free cortisol     

Ectopic Acth-Secreting Syndrome: A Single-Center Experience

ObjectiveEctopic adrenocorticotropic hormone (ACTH)-secreting syndrome (EAS) is a rare cause of ACTH-dependent endogenous hypercortisolism. The objective of this study was to analyze clinical, biochemical, and imaging characteristics; management strategies; and outcomes of EAS patients.MethodWe screened the records (1993-2012) of ACTH-dependent endogenous hypercortisolism cases managed at a tertiary care center.ResultsOf the 218 patients, 17 were diagnosed with EAS. The median 8:00 AM serum cortisol was 36 μg/dL (11.4-82.7 μg/dL), and the median basal plasma ACTH was 156 pg/mL (53.5-468 pg/mL). Notably, ACTH levels below 100 pg/mL were found in 4 patients. Suspicious microadenoma was found on magnetic resonance imaging (MRI) of the pituitary in 5 patients, and all of them underwent transsphenoidal surgery (TSS). Inferior petrosal sinus sampling (IPSS) was performed in 8 patients, and the results were suggestive of a peripheral source in all 8. Computed tomography (CT) localized the lesion in 15/17 patients. In 2 patients with negative CTs, gallium DOTATATE positron emission tomography (PET) scans localized the lesion. Despite difficulties localizing bronchial carcinoids, the cure rate was high (72%). In contrast, thymic carcinoids were easily localized but had poor outcomes.ConclusionEAS cannot be ruled out on the basis of marginally elevated ACTH. In cases with an equivocal MRI pituitary finding, prior IPSS can help avoid unnecessary TSS. CT is a useful modality for localization of an ectopic source. Functional imaging may help in cases where anatomical imaging fails. (Endocr Pract. 2013;19:1007-1014)     

Clinical Presentation and Long-Term Outcome of Patients With Ectopic Acth Syndrome Due to Bronchial Carcinoid Tumors: A One-Center Experience

Objective: To describe the diagnostic features and long-term outcome of patients with bronchial carcinoid tumors with ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS), treated in our department.Methods: We studied 10 cases with EAS and histologically confirmed bronchial carcinoid tumors, diagnosed from 1992 until 2006. Diagnosis was based upon blood, urine, radiologic, and interventional tests. Disease status at the time of the last follow-up was the primary outcome measure.Results: Clinical manifestations included Cushingoid features (100%), psychiatric symptoms (90%), hypertension (70%), diabetes/impaired glucose tolerance (40%), osteoporosis (10%), and hypokalemia (10%). The average time from the onset of symptoms until diagnosis was 14.2 ± 17.0 months. None of the patients exhibited a positive cortisol or ACTH response to corticotropin-releasing hormone (CRH) test, and none showed a positive gradient on bilateral inferior petrosal sinus sampling (BIPSS). All tumors were identified by computed tomography and by octreotide scintigraphy in 8 patients. All patients underwent surgical resection of the tumor, and 2 patients had adjuvant radiation therapy. The mean follow-up was 126.6 ± 63.3 months. At latest follow-up, 8 patients were in remission and 2 had recurrence of the EAS; both had a multifocal tumor. The 2 patients submitted to adjuvant radiation therapy were in remission at their latest follow-up, despite local invasion and lymph node metastases.Conclusion: CRH test and BIPSS are the most useful methods in diagnosing EAS. For localization, repeated imaging studies are necessary. Surgical treatment is effective in most cases. Adjunctive radiotherapy may be useful in patients with lymph node metastases. Patients with multifocal disease should be monitored for potential recurrence.Abbreviations: ACTH = adrenocotricotropic hormone BC = bronchial carcinoid BIPSS = bilateral inferior petrosal sinus sampling CD = Cushing disease CRH = corticotropin-releasing hormone CS = Cushing syndrome CT = computed tomography EAS = ectopic ACTH syndrome HDDST = high-dose dexamethasone suppression test HPA = hypothalamic-pituitary-adrenal IPS:P = inferior petrosal sinus to periphery ratio MRI = magnetic resonance imaging     

A Case of Occult Ectopic Adrenocorticotropic Hormone-Secreting Tumor: Diagnostic and Management Dilemmas

ObjectiveTo report a case of ectopic adrenocorticotropic hormone (ACTH) syndrome in a patient whose tumor was not localized by radiographic or biochemical means and to discuss the difficulties inherent in this patient’s care, illustrative of the challenges encountered by clinicians faced with similar cases.MethodsWe describe the clinical presentation of our case and discuss its management.ResultsA 49-year-old woman presented with symptoms and physical findings strongly suggestive of Cushing syndrome. Findings on biochemical evaluation were consistent with ectopic ACTH syndrome. Radiographic imaging did not clearly identify a discrete tumor. Bilateral inferior petrosal sinus sampling and whole-body selected venous sampling were unsuccessful in localizing the source of ACTH secretion. Surgical exploration was undertaken with use of intraoperative ultrasonography. Both a primary tumor and metastatic disease were identified, and the patient underwent distal pancreatectomy and splenectomy, as well as sequential bilateral adrenalectomy. The primary lesion was a neuroendocrine tumor that did not stain positive for ACTH. Chemotherapeutic agents were used to control bulky hepatic metastatic lesions until the patient’s demise 2½ years after her initial presentation.ConclusionThis case illustrates the difficulties encountered in the assessment and management of a patient with ectopic ACTH syndrome when conventional methods of tumor localization fail to identify the source of hormone secretion. (Endocr Pract. 2008;14:588-591)     

Adrenal Cortical Carcinoma With Late Pulmonary Metastases Causing Clinicical Cushing’s Syndrome: Case Report With Immunohistochemical Analysis Of Steriodogenic Enzyme Production

ObjectiveTo present a case of pulmonary metastases from adrenocortical carcinomas (ACC) that were secreting fully-functional cortisol resulting in clinical Cushing’s syndrome and to compare the steroidogenic enzyme expression in the primary tumor and lung.MethodsWe analyzed and summarized the patient’s medical history, physical examination results, labora tory data, imaging studies, and histopathologic results. The original tumor and the pulmonary metastases were then immunohistochemically evaluated for steroidogenic enzymes.ResultsInitial endocrinological workup revealed hyperandrogenism and adrenocorticotropic hormone (ACTH) independent Cushing’s due to a 4 cm left adrenal mass. The patient was initially diagnosed with an adrenal adenoma. Four years later, the patient developed recurrent Cushing’s syndrome. Repeat magnetic resonance imaging (MRI) showed no adrenal masses; however, chest computed tomography (CT) showed multiple bilateral lung nodules and biopsy revealed metastases of adrenal origin. Upon immunohistochemical analysis, side chain cleavage, 17α hydroxylase, 3β hydroxysteroid dehydrogenase, and 21 hydroxylase immunoreactivity were detected in both the original and pulmonary metastatic lesions with patterns of disorganized steroidogenesis. Dehydroepiandrosterone sulfotransferase (DHEA-ST) immunoreactivity was detected in the original tumor but not in the lung metastases.ConclusionThis case demonstrates some inter esting features of ACC that pose challenges to its management, including the difficulties in establishing the pathologic diagnosis, the potential for fullyfunctional steroidogenesis even in late metastases, and the plasticity of steroidogenic potential in tumor cells. (Endocr Pract. 2012;18:e138-e143)     

Bilateral Adrenalectomy: Lifesaving Procedure in Severe Cushing Syndrome

ObjectiveTo discuss the role of bilateral adrenalectomy in Cushing syndrome, as illustrated in a case of severe hypercortisolism that was unresponsive to combination agent medical therapy.MethodsWe report the clinical, laboratory, imaging, and pathologic findings in a patient with ectopic Cushing syndrome attributable to an adrenocorticotropic hormone (ACTH)-secreting neuroblastoma. In addition, we provide a literature review regarding olfactory neuroblastoma and discuss current and emerging therapeutic options for Cushing syndrome.ResultsA 59-year-old man presented with nasal congestion and neck swelling and was noted to have hypokalemia, hypertension, and hyperglycemia. A nasal biopsy demonstrated a poorly differentiated carcinoma with neuroendocrine features. He was subsequently diagnosed as having ACTH-dependent Cushing syndrome, but despite high-dose combination medical therapy, his condition rapidly deteriorated. Urgent bilateral adrenalectomy provided rapid control of the hypercortisolism, and the patient was later able to undergo an uncomplicated total macroscopic resection of his locally metastatic primary tumor.ConclusionThis report describes the challenges in the diagnosis and management of ACTH-dependent Cushing syndrome and highlights the important role that bilateral adrenalectomy can still have in patients with severe hypercortisolism causing life-threatening complications. (Endocr Pract. 2012;18:e85-e90)     

An Unusual Variant of Cushing Syndrome

ObjectiveTo discuss the initial clinical manifestations of primary pigmented nodular adrenocortical disease.MethodsWe present a case report of a 4-year-old boy who had the classic clinical features of Cushing syndrome. Results of hormonal investigations are reviewed, and histopathologic findings are illustrated.ResultsInvestigations revealed adrenocorticotropic hormone (corticotropin)-independent Cushing syndrome. Findings on magnetic resonance imaging of the pituitary gland and abdomen were within normal limits. The patient underwent bilateral adrenalectomy. The histopathologic features were consistent with primary pigmented nodular adrenocortical disease.ConclusionPrimary pigmented nodular adrenocortical disease should be suspected in patients with corticotropin- independent Cushing syndrome who have normal findings on adrenal imaging. (Endocr Pract. 2008;14:717-720)     

Etiology-, Sex-, and Tumor Size-Based Differences in Adrenocorticotropin-Dependent Cushing Syndrome

ObjectiveTo examine demographic, clinical, and biochemical differences in patients with adrenocorticotropin (ACTH)-dependent Cushing syndrome (CS) based on etiology, sex, and tumor size.MethodsThis was a single-center study of 211 patients with ACTH-dependent CS followed for 35 years. Patients were stratified into 3 groups based on etiology: Cushing disease (CD)/transsphenoidal surgery, Cushing disease/total bilateral adrenalectomy (CD/TBA), and ectopic ACTH secretion (EAS). Patients were also stratified based on sex and tumor size (nonvisualized, microadenoma, and macroadenoma).ResultsCD was the commonest cause of ACTH-dependent CS (190; 90%). Most patients presented in the third decade (median age, 29 years). Clinical features, cortisol, and ACTH were significantly greater in the EAS group. The CD/TBA group had more nonvisualized tumors (22% vs 8%; P = .000) and smaller tumor size (4 vs 6 mm; P = .001) compared with the CD/transsphenoidal surgery group. There was female predominance in CD (2.06:1) and male predominance in EAS (2:1). Men had shorter duration of symptoms (2 years; P = .014), were younger (23 years; P = .001), had lower body mass index (25.1 kg/m²; P = .000), and had more severe disease (low bone mineral density, hypokalemia). Macroadenomas were frequent (46; 24.2%), and ACTH correlated with tumor size in CD (r = 0.226; P = .005).ConclusionOur cohort presented at an earlier age than the Western population with a distinct, but slightly lower, female predilection. Patients with CD undergoing TBA had frequent negative imaging. Men had a clinical profile suggesting aggressive disease. Microadenoma and macroadenoma were difficult to distinguish on a clinicobiochemical basis.     

Cushing’s Disease and Pregnancy: Case Report and Literature Review

ObjectiveTo describe a patient with untreated Cushing’s disease who had 2 spontaneous pregnancies that resulted in healthy babies on both occasions.MethodsWe present a case report with clinical, laboratory, and imaging data and discuss the literature pertaining to pregnancy in patients with Cushing’s syndrome.ResultsA 28-year-old woman came to our endocrinology clinic with a 1-year history of symptoms and signs of Cushing’s syndrome. An elevated 24-hour urinary cortisol excretion and an unsuppressed 1-mg overnight dexamethasone test confirmed the diagnosis. On her next visit, she reported a confirmed pregnancy, which ultimately resulted in the birth of a normal child. Further work-up subsequently showed 2 elevated 24-hour urinary cortisol values, loss of diurnal variation, and an elevated corticotropin level. There was lack of suppression on low-dose and high-dose overnight dexamethasone suppression tests. Magnetic resonance imaging of the pituitary showed normal findings. Inferior petrosal sinus sampling was recommended, but she declined the procedure. The patient returned 3 years later for reevaluation, at which time she reported the birth of another healthy child by cesarean delivery 10 months previously. There were no reported maternal or fetal complications. Examination at this visit revealed buccal pigmentation and proximal myopathy. Investigations showed increased 24-hour urinary cortisol excretion and serum corticotropin levels. Repeated magnetic resonance imaging disclosed a microadenoma on the right side of the pituitary. Unstimulated inferior petrosal sinus sampling showed a gradient to the right; thus, the presence of pituitary-dependent Cushing’s disease was confirmed.ConclusionOur case demonstrates that patients with pituitary-dependent Cushing’s disease are more likely to have spontaneous pregnancies with favorable outcomes than are patients with Cushing’s syndrome due to other causes. Our patient, despite having Cushing’s disease for more than 7 years, had 2 uneventful pregnancies that produced normal healthy children, without exacerbation of her disease during pregnancy. (Endocr Pract. 2007;13: 296-299)     

Iatrogenic Cushing Syndrome in Patients Receiving Inhaled Budesonide and Itraconazole or Ritonavir: Two Cases and Literature Review

ObjectiveTo present two cases of iatrogenic Cushing syndrome caused by the interaction of budesonide, an inhaled glucocorticoid, with ritonavir and itraconazole.MethodsWe present the clinical and biochemical data of two patients in whom diagnosis of Cushing syndrome was caused by this interaction. We also reviewed the pertinent literature and management options.ResultsA 71-year-old man was treated with inhaled budesonide for a chronic obstructive pulmonary disease and itraconazole for a pulmonary aspergillosis. The patient rapidly developed a typical Cushing syndrome complicated by bilateral avascular necrosis of the femoral heads. Serum 8:00 AM cortisol concentrations were suppressed at 0.76 and 0.83 µg/dL on two occasions. The patient died 4 days later of a massive myocardial infarction. The second case is a 46-year-old woman who was treated for several years with inhaled budesonide for asthma. She was put on ritonavir, a retroviral protease inhibitor, for the treatment of human immunodeficiency virus (HIV). In the following months, she developed typical signs of Cushing syndrome. Her morning serum cortisol concentration was 1.92 µg/dL. A cosyntropin stimulation test showed values of serum cortisol of <1.10, 2.65, and 5.36 µg/dL at 0, 30, and 60 minutes, respectively, confirming an adrenal insufficiency. Because the patient was unable to stop budesonide, she was advised to reduce the frequency of its administration and eventually taper the dose until cessation.ConclusionClinicians should be aware of the potential occurrence of iatrogenic Cushing syndrome and secondary adrenal insufficiency due to the association of inhaled corticosteroids with itraconazole or ritonavir. (Endocr. Pract. 2013;19:e138-e141)     

Low Diagnostic Utility of Overnight High-Dose Dexamethasone Suppression Test in ACTH-Dependent Cushing’s Syndrome

ObjectiveOvernight high-dose dexamethasone suppression test (ON-HDDST) is a simple test to localize the source of ACTH in patients with ACTH-dependent Cushing’s syndrome (CS). However, previous studies have reported its varying accuracy. We studied the utility of ON-HDDST in diagnosing Cushing’s disease (CD) in a series of patients with CD and ectopic ACTH syndrome (EAS).MethodsWe conducted a retrospective study of 88 patients with ACTH-dependent CS (plasma ACTH > 20.0 pg/mL), who underwent an ON-HDDST. CD and EAS were diagnosed in 68 and 20 patients, respectively. Patients were investigated using MRI of the sellar region, CT of the thorax/abdomen, Gallium-68-DOTANOC PET scan, and bilateral inferior petrosal sinus sampling as required.ResultsPatients with EAS had a significantly higher serum cortisol after ON-HDDST than patients with CD (median [IQR], 19.9 [12.4-31.1] μg/dL vs 9.9 [5.1-25.0] μg/dL, P <.01). A suppressed ON-HDDST (≥50% fall from baseline) was noted in 44 (65%) patients with CD and 3 (15%) patients with EAS (P <.0001). Among patients with CD, cortisol suppression >50% was noted in 35 (76%) of patients with microadenoma and 7 (44%) with macroadenoma. Among patients with EAS, ON-HDDST was suppressed in 1 of 6 patients (17%) with an occult tumor and 2 of 14 patients (14%) with a localized tumor. The ROC curve plotted for the percentage suppression of cortisol had an area under the curve (AUC) of 0.72 (P =.01). The best test parameters, with 65% sensitivity, 85% specificity, 94% positive predictive value, 42% negative predictive value, and 69% accuracy, were at 50% cutoff level.ConclusionThe ON-HDDST had a poor diagnostic value in differentiating CD and EAS.     

Diagnosis by Serendipity: Cushing Syndrome Attributable to Cortisol-Producing Adrenal Adenoma as the Initial Manifestation of Multiple Endocrine Neoplasia Type 1 Due to a Rare Splicing Site Men1 Gene Mutation

ObjectiveTo report a case that highlights the potential for Cushing syndrome to be the first manifestation of multiple endocrine neoplasia type 1 (MEN 1) syndrome and to describe the rare underlying genetic mutation and the heterogeneous manifestations of the syndrome within the same family.MethodsWe present a case report including biochemical and radiologic findings, review family data, and discuss the results of genetic analyses.ResultsA 16-year-old girl who was not known to have any medical illness and had no known family history of MEN 1 syndrome presented with Cushing syndrome attributable to a cortisol-producing adrenal adenoma. During her evaluation, she was found to have primary hyperparathyroidism and a pituitary microprolactinoma. These findings raised the possibility of MEN 1 syndrome. She did not have clinical, biochemical, or radiologic evidence of islet cell pancreatic tumors. Family screening showed that her father had evidence of primary hyperparathyroidism, mild hyperprolactinemia, normal findings on magnetic resonance imaging of the pituitary, and a 1.2- cm nodule in the tail of the pancreas in conjunction with slight elevation of serum insulin and normal gastrin levels. The patient’s 5 siblings had evidence of primary hyperparathyroidism, and 2 of them also had mild hyperprolactinemia. Genetic screening confirmed the presence of a MEN1 gene missense G to A mutation in the patient, her father, and her siblings at the splicing site of intron 6 (IVS6 + 1G > A). This mutation leads to frameshift and truncation of the MEN1 gene.ConclusionIn MEN 1, Cushing syndrome is an extremely rare and usually late manifestation. Most cases are due to corticotropin-producing pituitary adenomas. Although Cushing syndrome generally develops years after the more typical manifestations of MEN 1 appear, it may be the primary manifestation of MEN 1 syndrome. There is considerable heterogeneity in the manifestations of MEN 1, even within a family having the same genetic mutation. (Endocr Pract. 2008;14:595-602)     

Cushing Syndrome Secondary to A Thymic Carcinoid Tumor Due to Multiple Endocrine Neoplasia Type 1

ObjectiveTo present an Iranian patient with a nonclassic form of multiple endocrine neoplasia type 1 (MEN 1) who presented with ectopic Cushing syndrome (CS) secondary to a corticotropin (ACTH)-producing thymic neuroendocrine tumor (NET), recurrent renal stones, and a giant cell granuloma of the jaw due to primary hyperparathyroidism (PHPT) without involvement of the pituitary or pancreas.MethodsRelevant imaging and hormonal evaluations were performed. The patient was operated on 2 occasions for a thymic NET and on 3 occasions for PHPT. DNA from a peripheral blood sample was extracted for sequencing of the MEN1 gene.ResultHistopathologic evaluation of the thymic tumor removed during the first surgery showed an atypical carcinoid tumor with a Ki-67 labeling index of 5%. Evaluation after the second surgery revealed an invasive carcinoid tumor with a Ki-67 labeling index of 30%.Parathyroid pathology was suggestive of glandular hyperplasia. Menin gene sequencing revealed a novel frameshift mutation c.1642_1648dup in exon 10.ConclusionThis case of MEN 1 is unusual because most thymic NETs in MEN 1 are nonfunctional, and secretion of ACTH or other ectopic hormones rarely occurs. In patients presenting with thymic NETs, the possibility of MEN 1 should be considered, especially in the presence of hyperparathyroidism. This case also demonstrates that the behavior of thymic NETs can change over time from slow-growing tumors to highly invasive neoplasia, and that ectopic ACTH can be produced by these tumors in the context of MEN 1. (Endocr Pract. 2011;17:e92-e96)     

Medullar thyroid carcinoma in mediastinum initially presenting as Ectopic ACTH syndrome. A case report

A rare case with ectopic adrenocorticotrophic hormone syndrome (EAS) caused by medullar thyroid carcinoma (MTC) in mediastinum was reported. This 49 year-old male patient initially presented with serious and intractable hypokalemia. Endocrine evaluations showed increased levels of adrenocorticotrophic hormone (ACTH) and urinary free cortisol, which could not be suppressed more than 50% by high-dose dexamethasone suppression test. Computed tomography (CT) scan detected a 5×5×5?cm mass at the bottom of thyroid in anterior mediastinum. The patient underwent total thyroidectomy with central compartment and ipsilateral modified radical neck dissection. Pathological examination showed an infiltrating thyroid medullary carcinoma with abundant amyloid deposition, meanwhile immunohistochemical positive for ACTH. After surgery, serum levels of kalium, as well as cortisol and ACTH returned to normal range. During follow-up, the patient's clinical manifestation of Cushing syndrome relieved.