Ectopic ACTH-producing Tumors Research Articles

FRI371 Serum Androstenedione As An Additive Biomarker In Ectopic Cushing’s Syndrome Evaluation

Abstract Disclosure: S. Zhang: None. J.C. Lo: None. M.G. Jaffe: None. H. Arzumanyan: None. Background: Ectopic Cushing’s syndrome (ECS) results from glucocorticoid excess secondary to ectopic ACTH or CRH producing tumors. Although ECS identification can be challenging when presentation lacks classic Cushing’s features, ectopic ACTH secretion can result in a key constellation of findings that facilitate early clinical recognition. We describe a case of ECS from an ACTH-producing carcinoid tumor of the lung presenting with resistant hypertension, severe hypokalemia, and muscle weakness. In addition to significant hypercortisolism, laboratory findings were notable for high androstenedione levels without concomitant increase in DHEAS and testosterone levels. Case: A 59-year-old female athlete with history of well-controlled hypertension developed difficult to control hypertension, requiring escalation to triple antihypertensive therapy within 3 months. During this time, she had multiple emergency department visits for progressive muscle weakness, hypertension, and persistent hypokalemia despite potassium supplementation. She was hospitalized for further evaluation. Physical examination was notable for bruising, muscle wasting, thin extremities, facial fullness, and disproportionate abdominal adiposity. Workup for Cushing’s syndrome demonstrated ACTH-dependent hypercortisolism and markedly elevated androstenedione 398 ng/dL (normal 20-75 ng/dL) despite normal DHEAS 48 mcg/dL (normal <430 mcg/dL) and total testosterone 11 ng/dL (normal <45 ng/dL) levels. A chest CT identified a 3.8 cm right lower lobe lung mass and transbronchial biopsy confirmed atypical carcinoid tumor. She underwent a right middle and lower lobe bilobectomy with complete tumor resection. Cortisol, androstenedione, and potassium levels rapidly normalized postoperatively, and blood pressure returned to baseline, well-controlled on monotherapy. The patient only required 3 days of hydrocortisone therapy for transient steroid withdrawal symptoms. Conclusions: Our case illustrates a difficult to diagnose uncommon disease presenting with resistant hypertension, hypokalemia and marked androstenedione elevation despite normal DHEAS and testosterone levels. This steroidogenic profile has been reported in other ECS cases and attributed to differential effects of ectopic ACTH production on adrenal androgen biosynthesis (1). Although ECS is rare and the primary lesion can be difficult to identify, disproportionate elevation in androstenedione may prompt recognition of ECS and support early detection and management. Reference: (1) Barbetta L, Dall’Asta C, Re T, Colombo P, Travaglini P, Ambrosi B. Androgen secretion in ectopic ACTH syndrome and in Cushing’s disease: modifications before and after surgery. Horm Metab Res Horm Stoffwechselforschung Horm Metab. 2001;33(10):596-601 Presentation: Friday, June 16, 2023

ODP278 A rare case of Ectopic ACTH secretion associated with Primary Gastric Choriocarcinoma

Abstract Background Ectopic ACTH production contributes to 10-15% of cases of Cushing's syndrome. Most cases are caused by neuroendocrine tumors of the lung, pancreas, or thymus. Other rare tumors causing ectopic ACTH secretion include esophageal tumor, gastric carcinoid tumor and squamous cell carcinoma of the larynx (1). We present a rare case of ectopic ACTH production causing Cushing syndrome due to primary gastric choriocarcinoma. Case Presentation A 27-year-old lady, not known to have any chronic illnesses, presented with two days history of epigastric pain. The patient also reported facial puffiness, leg swelling, generalized weakness and oligomenorrhea for the last four months. There was no history of easy bruisability or weight. She was not taking any medications. The patient did not smoke or use alcohol. Physical examination revealed conjunctival pallor, facial acne, wide striae on her thighs and hepatomegaly. The rest of the examination was normal. Lab tests showed microcytic anemia with hemoglobin of 7 gm/dl (12-15 gm/dl), hypokalemia (2.5 mmol/L; normal 3.5-5.3 mmol/L), AST 38 U/L (0-40 U/L) and ALT 45 U/L (0-41 U/L). β HCG was 1,506 mIU/mL (0 -5 mIU/ml). An abdominal ultrasound showed hepatomegaly with multiple echogenic solid mass lesions suspicious of metastatic origin. A CT abdomen showed a solid lesion in the fundal region of the stomach with multiple liver metastases and moderate ascites. An esophagogastroduodenoscopy showed fungating mass originating from the stomach fundus. Biopsy of the gastric mass revealed primary gastric adenocarcinoma, which was positive forCK 7, CK 19, beta hCG, CDX2 and CEA, consistent with the diagnosis of primary gastric choriocarcinoma. Due to widespread metastasis, the patient was started on palliative chemotherapy with dexamethasone 2 mg injection once daily along with capecitabine, cisplatin and pembrolizumab. In view of persistent hypokalemia and physical examination findings, a workup for Cushing's syndrome was performed. Early-morning serum cortisol was 1054 nmol/L (138–689 nmol/L), and plasma ACTH was 174 pg/ml (7.2-63.3 pg/ml) despite the patient being on intravenous 2 mg dexamethasone once daily for more than ten days. An MRI of the brain showed a normal pituitary gland. Based on these findings, the patient was diagnosed with Cushing's syndrome due to ectopic ACTH secretion. Unfortunately, her hospital course was complicated by massive upper gastrointestinal bleeding from the tumor, leading to her demise. Conclusion Gastric choriocarcinoma is a rare tumor associated with ectopic ACTH secretion leading to Cushing's syndrome. Reference: Imura H, Matsukura S, Yamamoto H, Hirata Y, Nakai Y. Studies on ectopic ACTH-producing tumors. II. Clinical and biochemical features of 30 cases. Cancer. 1975 May;35(5): 1430-7 Presentation: No date and time listed

PMON102 Utility of the Desmopressin Stimulation Test to Detect Cyclic Cushing's Disease

Abstract Background Arginine-vasopressin stimulates pituitary ACTH secretion after binding to arginine-vasopressin receptor 1B on corticotropes. Desmopressin (DDAVP), which preferentially binds to arginine-vasopressin receptor 2, stimulates the release of ACTH in most patients with pituitary corticotrope adenomas (Cushing's disease, CD), but not in most patients with ectopic ACTH-producing tumors or healthy people. Cyclic CD is characterized by periods of normal or low cortisol and ACTH, interspersed with hypercortisolism. We postulated that the DDAVP stimulation test, with measurement of ACTH and cortisol after a 10 mcg injection of DDAVP, might confirm the presence of an ACTH-producing pituitary adenoma even during periods without hypercortisolemia. Clinical Case A 27-year-old woman was diagnosed with Cushing's disease one year after developing weight gain, striae, intermittent acne, balding, irregular menses, a dorsal fat pad and facial rounding. Pituitary MRI revealed a right-sided 7 mm microadenoma; inferior petrosal sinus sampling confirmed a pituitary source of ACTH. Transsphenoidal resection was performed 6 months later. Histology showed an ACTH-positive adenoma and cortisol levels fell to 33nmol/L (1.2 ug/dL). Ten months later, due to intermittent symptoms, testing confirmed elevated UFC, with midnight cortisol of 565 nmol/L (20.3 ug/dL). Pituitary MRI showed a new right-sided lesion, interpreted as a residual adenoma or postoperative changes. Repeat surgical resection was recommended. She presented to our institution for a second opinion. On evaluation three weeks after recurrent hypercortisolism was confirmed, ACTH was low-normal (11.9 pg/mL, RR 5.0-46.0) and serum cortisol was undetectable. This rapid decrease was thought to signify apoplexy of the remaining adenoma or cyclic Cushing's disease. An MRI excluded apoplexy. However, surgery seemed inappropriate given hypocortisolism. To evaluate for the possibility of cyclic Cushing's disease due to residual adenoma, we performed a DDAVP stimulation test. This showed significant increases in ACTH and cortisol levels from 0 min to a 30-minute peak (ACTH 31.6 to 73.1 pg/mL, 131% increase, nl <50%; cortisol 2.6 to 8.1 mcg/dL [72 - 225 nmol/L], 212% increase, nl <20%). This led to transsphenoidal resection of a right-sided lesion. Cortisol levels were undetectable on post-operative day 3 and pathology showed an ACTH-producing adenoma. One week postoperatively, a repeat DDAVP stimulation test showed an insignificant rise in ACTH, and undetectable cortisol throughout (ACTH 11.1 to 12.4 pg/mL, 12% increase; cortisol <1.0 mcg/dL, 0% increase), which was deemed to indicate successful resection of the residual adenoma. She continues to lose weight and her clinical features of cortisol excess are involuting. Conclusion This case demonstrates how the DDAVP stimulation test can be used to both confirm the presence of ACTH-producing pituitary adenomas and assess the response to surgical resection. It may be particularly useful in the setting of cyclic Cushing's disease when cortisol and ACTH levels are not persistently elevated. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Bilateral Adrenalectomy: Differences between Cushing Disease and Ectopic ACTH-Producing Tumors.

Bilateral adrenalectomy (BA) is a curative treatment for hypercortisolism in patients with corticotropin (ACTH)-dependent Cushing syndrome. Indications include refractory Cushing'sdisease (CD) following failed pituitary surgery, and occult or unresectable ectopic ACTH-producing neoplasms (EA). This was a single-center, retrospective review (1995-2017) of patients undergoing BA for CD or EA. Demographics, laboratory findings, and intraoperative and postoperative variables were analyzed. Of 137 patients, 83 (61%) had CD and 54 (39%) had EA; 87% of CD patients were female versus 46% of EA patients (p < 0.0001). Mean age at diagnosis was 40 ± 15years for CD and 49 ± 18years for EA (p = 0.004). Preoperative serum cortisol concentrations were higher in the EA cohort (63 ± 40μg/dL) versus the CD cohort (33 ± 19μg/dL) [p < 0.001], with no significant differences in serum ACTH. Time from diagnosis until adrenalectomy was 54 ± 69months for CD versus 4 ± 13 for EA (p = 0.002). Most patients underwent minimally invasive surgery (MIS; 86% CD vs. 75% EA; p = 0.19). There was no difference between the rates of conversion to an open approach, intraoperative blood loss, or operative time between groups, and no difference between complications in CD versus EA (p = 1.0). Five-year survival was significantly shorter among the EA cohort (30% for EA vs. 80% for CD; p < 0.001). Patients with EA presented with higher serum cortisol levels compared with patients with CD. EA patients were more likely to require intraoperative transfusion and postoperative intensive care. BA in patients with CD and EA can be performed safely in an MIS fashion, with similar morbidity; however, survival at 5years was significantly less in the EA cohort.

Serum steroid profiling in Cushing’s syndrome patients

ContextCushing’s syndrome is caused by increased exposure to cortisol. Discrimination of different causes of endogenous hypercortisolism can make a diagnostic dilemma. Patients and MethodsIn serum samples from patients with Cushing’s syndrome (47 with Cushing’s disease, 6 with ectopic ACTH-dependent Cushing’s syndrome, 16 with adrenal adenoma, 7 bilateral adrenal hyperplasia (BMAH) with overt Cushing’s syndrome, 42 controls from the general population) using novel method based on gas chromatography-tandem mass spectrometry (GC–MS/MS) we measured 94 serum steroids to search for steroid fingerprint of each subtype. ResultsPatients with Cushing’s disease and ectopic ACTH producing tumors showed elevated levels of androgens and their metabolites when compared with healthy controls. Mineralocorticoid precursors were also elevated in ectopic ACTH syndrome. The levels of androgens were decreased in adrenal adenomas and BMAH. ROC analysis showed 100% sensitivity and 93.6% specificity for 11β-hydroxyepiandrosterone sulfate for discrimination of Cushing’s disease from ectopic ACTH secretion. We didn’t find any significant (p < 0.05) difference in steroids that would discriminate BMAH from unilateral adenomas causing Cushing’s syndrome. ConclusionVarious causes of Cushing’s syndrome show particular steroid fingerprints that can be used to discriminate and may help to achieve appropriate clinical diagnosis.

The incidence of endogenous Cushing's syndrome in the modern era.

Epidemiological studies on the incidence of Cushing's syndrome (CS) are few and most often includes only patients with the most common form, that is Cushing's disease (CD). To analyse the incidence of endogenous CS in an unselected cohort of patients from western Sweden between 2002 and 2017. Medical records from patients who had received a diagnostic code for CS and adrenocortical carcinoma in the Västra Götaland County between 2002 and 2017 were reviewed. Eighty-two patients had been diagnosed with endogenous CS in the region during the study period and were included in this analysis. Thirty-nine patients (48%) had CD, 21 (26%) had ectopic ACTH-producing tumour, 17 (21%) had a benign adrenal CS, and 5 (6%) had cortisol-producing adrenocortical carcinoma. Nine of 21 (43%) patients with ectopic CS had an ACTH-producing lung tumour, 4 had a neuroendocrine pancreas tumour, and 5 had an occult tumour. The annual incidence of endogenous CS was 3.2 cases per million/y; 1.5 for CD, 0.8 for ectopic CS, 0.7 for benign adrenal CS and 0.2 for adrenocortical carcinoma. Approximately three new cases of endogenous CS, per one million inhabitants, were diagnosed annually between 2002 and 2017. Compared with previous reports, proportionally more patients had ectopic CS. The reason for this is unclear although increased awareness of hypercortisolism in patients with malignant tumours in the modern era is a possible explanation.

SUN-333 Expression of Type 2 Somatostatin Receptors and Low Tumor Markers of Aggressiveness Correlate with Positive 68Ga-DOTATATE Findings in Ectopic ACTH-Producing Tumors

Background: Ectopic ACTH Syndrome (EAS) is caused by over production of ACTH from non-pituitary neuroendocrine tumors (NET). Tumor localization is challenging; lesions are often < 1 cm in diameter or slow growing so that they are not seen on thin-cut CT or FDG-PET. The use of functional imaging such as 68Ga-DOTATATE PET/CT (DOTATATE) and 6 mCi Octreoscan (OCT) takes advantage of somatostatin receptor expression on these NETs [1-3]. Here, we studied the type 2 somatostatin receptor (SSTR2) expression in ectopic ACTH-producing tumors by immunohistochemistry (IHC) and correlated it with DOTATATE and OCT findings. Methods: All 17 patients (pts) had anatomic and functional imaging and histologic confirmation of EAS. IHC of tumors included evaluation of ACTH, SSTR2 and Ki67; pancreatic tissue islets were the positive SSTR2 control. An experienced research pathologist scored positive staining by the distribution of staining throughout the tumor (diffuse or patchy/focal), the % of cells that were positive (as 1 – 30%, >30-<60% or >60%), and staining intensity (as 1-3). We correlated the IHC findings with imaging (positive or negative in tumor site) and aggressiveness markers in the area of greatest IHC staining, defined as the Ki67 index (<3%, >3-20%, or >20% positive), mitotic count in 10-25 high power fields (HPF), or presence of tumor necrosis or metastasis. Results: The median age at diagnosis was 50 ± 12 years, 65% were females (n:11/17), median tumor size 9 mm (range 4-67 mm). Tumor was identified by DOTATATE in 13/16 pts and by OCT in 3/17. All 17 resected tumors stained for ACTH. Tumor type and location included 11 pulmonary NETs (64%), and 1 each of pulmonary tumorlets, appendiceal NET, ovarian teratoma, mediastinal NET, pheocromocytoma and a NET in a lymph node with unknown primary. Ten tumors had 3+ SSTR2 staining in >75% cells; DOTATATE was positive for all, OCT detected only 3. Four tumors had 0 – 1% of SSTR2 positive cells; DOTATATE was positive in 2 and OCT in none. Three tumors had <10, <25 and 50% staining and 1-2+ intensity; DOTATATE detected 1 and OCT none. Both scans were negative in a mediastinal NET with necrosis, Ki67 >20%, 25 mitoses/10 HPF and <1% SSTR2+ cells, and a metastatic ovarian teratoma with Ki67 21%, mitotic count 21/10HPF and <25% SSTR2+ cells. Conclusions: Most EAS tumors in our cohort were small, expressed SSTR2, and lacked markers of aggressiveness. Strong SSTR2 expression correlated with positive 68Ga-DOTATATE findings in 100% of cases but only 33% of OCT cases. Negative or limited SSTR2 receptor distribution was associated with 43% rate of DOTATATE positivity. Further investigation is needed into expression of other SSTRs to understand this finding. We speculate that positive imaging is a complex reflection of tumor size, SSTR expression, and malignancy potential.

Spontaneous adrenocorticotropic hormone (ACTH) normalisation due to tumour regression induced by metyrapone in a patient with ectopic ACTH syndrome: case report and literature review

BackgroundEctopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is caused by tumours releasing ACTH. Ectopic ACTH-producing tumour regression is rarely induced using steroidogenesis inhibitors. We presented a case of EAS in which ACTH production by a lung tumour was reduced by metyrapone (MTP) and also reviewed previous cases of ectopic ACTH production suppressed via steroidogenesis inhibition.Case presentationA 71-year-old female with general fatigue, central obesity and impaired glucose tolerance was diagnosed with Cushing’s syndrome due to elevated ACTH (192.9 pg/mL; normal range, 7.2–63.3 pg/mL), cortisol (73.1 μg/dL; 6.4–21.0 μg/dL) and 24-h urinary free cortisol (UFC) (6160 μg/day; 11.2–80.3 μg/day) levels. Chest computed tomography identified a solid 26.6 × 22.9 × 30.0 mm tumour with a cavity in the upper lobe of the left lung. There was no adrenal gland enlargement. Tumour markers were not significantly elevated; ACTH levels were not suppressed by 8-mg dexamethasone. A corticotropin-releasing hormone stimulation test revealed blunted ACTH response (basal ACTH, 204.6 pg/mL; highest ACTH level during the 120-min stimulation test, 214.0 pg/mL). She was diagnosed with EAS due to a lung lesion. MTP treatment was started to reduce cortisol production. ACTH levels and cortisol and UFC levels were normalised and the ACTH-producing lung tumour was ablated after MTP treatment. In several reported cases, plasma ACTH levels reduced during steroidogenesis inhibitor treatment for EAS. Among the 10 patients, three cases of pheochromocytoma, one of thymic carcinoid and one of islet cell carcinoma were reported. In four cases, the tumour was not detected. In our case, the pathology of the lung tumour was unknown because of lack of tumour cells in biopsy. The patients were treated with ketoconazole (KTZ) and/or MTP and exhibited ACTH and cortisol/UFC suppression, but tumour regression was observed only in our case.ConclusionMTP and/or KTZ may reduce ACTH and cortisol production. The tumour spontaneously regressed after MTP treatment, indicating that MTP may reduce the tumour size without surgery. The mechanisms of therapeutic effects of steroidogenesis inhibitors and prognosis of spontaneous remission should be elucidated further via molecular biology studies.

Surgical treatment of ectopic adrenocorticotropic hormone syndrome with intra-thoracic tumor.

The study was to review the clinical manifestations and laboratory examinations of ectopic adrenocorticotropic hormone (ACTH) syndrome, and to analyze the efficacy of surgical treatment. The clinical data, surgical therapy, and outcome of 23 cases of ectopic ACTH syndrome accompanied by intra-thoracic tumors were reviewed. The tumors were removed from all the patients according to the principles of radical resection. The tumors were confirmed as associated with ectopic ACTH secretion in 19 cases. Hyperglycemia and hypokalemia were recovered, while plasma cortisol, plasma ACTH and 24-hour urinary free cortisol (UFC) levels were significantly reduced after surgery in these 19 cases. Recurrences of the disease were found in six cases during following-up, and five of them died. The thoracic cavity should be a focus in routine examinations of patients with symptoms of Cushing's syndrome (CS), because ectopic ACTH-producing tumors are commonly found in bronchus/lung and mediastinum. Despite the incidence of the pulmonary nodule secondary to opportunistic infection in some cases, surgery is still the first choice if the tumor is localized. The surgical procedure should be performed according to the principles in resection of lung cancer and mediastinal tumor. The surgical efficacy is significant for short-term periods; however, the recurrence of the disease in long-term periods is in great part related to distal metastasis or relapse of the tumor.

Neuroendocrine Tumor in Liver With Positive ACTH Receptor

A rare case of possible primary ectopic adrenocorticotropic hormone (ACTH)-producing tumor in the liver mimicking a liver hemangioma is reported. A 9-year-old boy, with Cushing syndrome, was referred for the assessment of ectopic ACTH-producing tumor. Ultrasound, CT scan, and MRI of the abdomen revealed a liver lesion suggestive of a hemangioma. (111)In-octreotide scintigraphy revealed focal activity in the liver, indicative of a somatostatin-positive lesion. (99m)Tc-labeled RBC scintigraphy was negative for hemangioma. After surgical resection of the tumor, the cortisol level converted to a normal range indicative of a rare possible primary ACTH-producing tumor in the liver, which was confirmed by histopathology.

The Value of Somatostatin Receptor Imaging with In-111 Octreotide and/or Ga-68 DOTATATE in Localizing Ectopic ACTH Producing Tumors

Objective: We aimed to evaluate the value of somatostatin receptor imaging (SRI) with In-111 octreotide and Ga-68 DOTATATE in localizing ectopic ACTH producing tumors.Methods: Nineteen patients who had In-111 octreotide somatostatin receptor scintigraphy (SRS) and/or Ga-68 DOTATATE PET-CT to localize ectopic ACTH producing tumors between the years 2000 and 2012 were included retrospectively in our study. The results of SRI were compared with clinical onset, radiological findings and surgical data of the patients.Results: Sixteen In-111 octreotide SRS and five Ga-68 DOTATATE PET-CT were performed in 19 patients. In eight out of 19 patients, ectopic ACTH secretion site could be detected. In five patients, SRS showed pathologic uptake. In four of these patients, surgery revealed pulmonary carcinoid tumors and in one patient pancreatic neuroendocrine tumor. In one patient, Ga-68 DOTATATE PET-CT revealed pathologic uptake in lung nodule which came out to be pulmonary carcinoid tumor. In another patient who had resection of metastases of atypical carcinoid tumor prior to scans, new metastatic foci were detected both with SRS and Ga-68 DOTATATE PET-CT imaging. In one patient, although SRS was negative, CT which was performed three years later showed a lung nodule diagnosed as pulmonary carcinoid tumor. In 11 patients, ectopic ACTH secretion site could not be detected. In 10 of those patients, scintigraphic and radiological imaging did not show any lesions and in one patient, Ga-68 DOTATATE PET-CT was false positive.Conclusion: SRI has a complementary role with radiological imaging in localizing ectopic ACTH secretion sites. PET-CT imaging with Ga-68 peptide conjugates is a promising new modality for this indication. Conflict of interest:None declared.

Fountain of steroid deep within: a case report of an ectopic ACTH-producing tumor

Fountain of steroid deep within: a case report of an ectopic ACTH-producing tumor

Methods of topical diagnosis of ectopic ACTH-producing tumors of different localization (review of the literature)

Topical diagnostic methods in ACTH-producing neuroendocrine tumors with various localization. Topical diagnostic of ACTH-producing neuroendocrine tumors is a major stage in management of patients with ACTH-producing syndrome, because one of the main methods of treatment of such patients is surgical. There are several methods of topical diagnostic of ACTH-producing tumors with ectopic ocalization which have some advantages and disadvantages. At the same time until now any of existing methods of research doesn't guarantee 100% result that leads to obtaining the false positive conclusions and, as a result, carrying out unreasonable surgical operation. This report is about the main methods of topical diagnosis and their comparative characteristics. Besides possible ways to increase sensitivity and efficiency of methods and improve results are discussed in article.

A Small Solitary Pulmonary Nodule Discovered by 18F-fluorodeoxyglucose Positron Emission Tomography and CT: Rare Infection Instead of Rare Tumor

THE causes of Cushing's syndrome are mainly divided into adrenocorticotropic hormone (ACTH) dependent and independent. ACTH dependent hypercortisolism represents excess ACTH se-creting by the pituitary or tumor outside the pituitary; and the latter one is also called as ectopic ACTH syndrome. Thorax is the most common location of causative lesions for ectopic ACTH syndrome, and the size of lesion is too small to be detected in some cases.1, 2 Cryptococcal pneumonia usually occurs in immunocompromised patients and excess cortisol production can theoretically produce a state of immunodeficiency. Development of cryptococcal pneumonia concomitant with Cushing syndrome (CS) was rare. Here, we report a case of pulmonary nodule in a patient with CS differentiated with ectopic ACTH-producing tumor. Cryptococcal pneumonia was diagnosed following lung resection.

A rare case of Cushing syndrome by cyclic ectopic-ACTH

ACTH-dependent Cushing syndrome (CS) due to ectopic ACTH production is most times difficult to manage. The identification of the source of ACTH may take many years. Surgery or chemotherapy for the primary tumor is not always possible. Control of Cushing symptoms is many times achieved using medication, or bilateral adrenalectomy in refractory cases. This case presents a Brazilian male who showed severe hypertension, mood changes, muscle weakness, darkening of skin, and increased abdominal fat. An investigation for Cushing syndrome was carried out and, after a four-year follow-up, a carotid glomus tumor (chemodectoma) was confirmed, a rare ectopic ACTH-producing tumor. Besides, the patient presented cyclic Cushing syndrome that was exacerbated by diverticulitis episodes. This case presents interesting pitfalls on diagnosis and management of ACTH-dependent CS. This is the only report of a chemodectoma that produced ACTH in the literature.

Pituitary Cyclic Cushing's Syndrome Concomitant with Solitary Cryptococcal Pneumonia Confused with Ectopic ACTH-producing Tumor

A 47-year-old man with Cushingoid appearance was admitted to our hospital showing excessive secretion of cortisol at intervals of a few days. Cyclic Cushing's disease was confirmed. Two years earlier, results of hormonal assessment had been within normal limits and macroadenoma had been incidentally detected in the pituitary. Dexamethasone suppression testing revealed various responses and a small lung tumor was detected, therefore his condition was misinterpreted as ectopic ACTH-producing tumor or pituitary cyclical Cushing's disease, leading to lung resection that confirmed cryptococcal pneumonia. The pituitary tumor was finally identified as the cause of cyclic Cushing's syndrome and fully removed, allowing remission.

Cyclic Cushing's syndrome

The cyclic Cushing's syndrome is a rare disease characterized by multiple episodes of elevated cortisol levels alternating with periods of its normal secretion. The so-called hypercorticism cycles may be either regular or episodic with intercycle intervals as long as a few days to several years. Most researchers agree that the reliable diagnosis of cyclic Cushing's syndrome should be based on laboratory detection of 3 peaks and 2 falls of plasma cortisol level. Cyclic Cushing's syndrome may be either ACTH dependent or independent. A review of 65 verified cases indicates that this condition may be caused by pituitary corticotropinoma (54%), ectopic ACTH-producing tumour (26%), and adrenal tumour (roughly 11%). The cause of the disease remains uncertain in 9% of the patients. Pathophysiological mechanisms of cyclic Cushing's syndrome are poorly known. In certain cases of bilateral macronodular adrenal hyperplasia or adrenal corticosteroma, it may be associated with the presence of ectopic receptors or anomalous expression of normally located receptors. The majority of the patients presenting with cyclic Cushing's syndrome exhibit symptoms of classical hypercorticism that manifest themselves either on a permanent or cyclic basis. In a small number of patients, clinical signs of cyclic Cushing's syndrome are virtually absent. Variations of the clinical picture and conflicting results of hormonal assays taken together make cyclic Cushing's syndrome difficult to diagnose. Therefore, physicians must be aware of this condition and actively search for it in all patients believed to have an enhanced cortisol production despite normal results of laboratory analysis. Frequent changes of urinary or salivary free cortisol levels are reliable and convenient criteria for cyclic Cushing's syndrome in patients suspected to have this condition. Results of cortisol stimulation or suppression tests are likely to lead to a false conclusion due to spontaneous falls and rises in serum cortisol levels at the time of analysis. Given laboratory confirmation of cyclic Cushing's syndrome, subsequent studies should be focused on the elucidation of its cause. The average life expectancy of patients with cyclic Cushing's syndrome remains to be determined.

Expression of somatostatin and dopamine receptors in ACTH-producing tumours

This study was designed to compare immunoexpression of somatostatin receptors (SR)1-5 and dopamine receptors 2 (DR2) in pituitary and non-pituitary ectopic ACTH-producing tumours. A total of 35 patients were enrolled in the study including 21 with Cushing's disease (CD) and 14 with ACTH-ectopic syndrome (ACTH-ES) associated with carcinoid tumours of lungs (n=11), kidney (n=1), thymus (n=1) and with small-cell lung carcinoma (n=1). All patients with corticotropinomas exhibited expression of SR 1-5 dominated by SR-1 (57%). 81% of these tumours expressed two and more SR subtypes. DR2 expression was documented in 52% of the tumours and co-expression of DR2 with different SR subtypes in 29%. Neoplasms associated with ACTH-ES expressed SR with the predominance of SR-3 (72%). Half of these tumours co-expressed two and more SR subtypes. Expression of DR2 was demonstrated in 50% of the neoplasms associated with ACTH-ES; 38% of them co-expressed SR and DF2.

Small-cell Carcinoma of the Endometrium Presenting as Cushing's Syndrome

Small-cell carcinoma (SCC) of neuroendocrine type is an uncommon tumor of the endometrium. No previous report has documented Cushing's syndrome due to ectopic ACTH production by SCC of the endometrium. We describe a 56-year-old Japanese woman with SCC of the endometrium and multiple lung metastases presenting as Cushing's syndrome. The patient was referred to our hospital because of general fatigue with facial and leg edema, and multiple nodular lesions in the bilateral lungs on chest X-ray examination. A physical examination revealed that the patient had moon face, buffalo hump, and truncal obesity. Endocrinological examinations confirmed ACTH-dependent Cushing's syndrome. Thoracic computed tomography imaging showed multiple nodular lesions in the bilateral lungs. Abdominal magnetic resonance imaging suggested a malignant tumor of the uterus. The patient received a lung tumor biopsy and surgical hysterectomy. The endometrial carcinoma was histologically a SCC admixed with endometrioid adenocarcinoma. The SCC of the endometrium showed immunoreactivity for pro-opiomelanocortin, ACTH, and vimentin, but not for thyroid transcription factor-1. The lung biopsy specimen had the same features. These findings indicated that the SCC originated from the endometrium, and the ectopic ACTH-producing tumor caused Cushing's syndrome. This study provides the evidence that SCC of endometrial origin was an ectopic ACTH-producing tumor causing Cushing's syndrome.

Processing of high-molecular-weight form adrenocorticotropin in human adrenocorticotropin-secreting tumor cell line (DMS-79) after transfection of prohormone convertase 1/3 gene

Ectopic ACTH-producing tumors preferentially secrete biologically inactive ACTH precursors and ACTH-related fragments. DMS-79 is known to secrete unprocessed high-molecular-weight (HMW) form ACTH. To determine whether prohormone convertase (PC) 1/3 is involved in the abnormal processing of proopiomelanocortin (POMC), we studied whether PC1/3 and 2 genes are expressed in DMS-79, and whether overexpression of PC1/3 gene affects POMC processing pattern. Steady-state mRNA levels of PC1/3 and 2 were determined by real-time RT-PCR. Molecular weights of ACTH-related peptides were determined by chromatographical analyses coupled with ACTH and beta-endorphin (beta-END) radioimmunoassays. PC1/3 gene was transfected into DMS-79 by retrovirus transduction using pMX-IP vector encoding PC1/3 cDNA. The steady-state mRNA levels of PC1/3 and 2 in DMS-79 were lower than those in ACTH-secreting and nonfunctioning pituitary tumors. DMS-79 predominantly secreted HMW form with both ACTH and beta-END immunoreactivities by size-exclusion chromatography. After purification by immunoaffinity chromatography with anti-ACTH antibody, the apparent molecular weight of HMW form ACTH was estimated to be 16 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis with silver staining. After retroviral transfection of PC1/3 cDNA into DMS-79 and puromycin selection, PC1/3 stably-expressing cell line (DMS-79T) secreted two immunoreactive ACTH components, a major one coeluting with ACTH(1-39) and a minor one as a HMW form as well as two beta- END immunoreactive components coeluting with beta-lipotropic hormone and beta-END, respectively. Thus, we have established PC1/3 stably-expressing cell line (DMS-79T) capable of proteolytically processing ACTH precursor molecule(s) into mature ACTH and beta-END.