Ectopic Source Of ACTH Research Articles

SAT598 7mg-dexamethasone Suppression Test For The Differential Diagnosis Of Cushing’s Syndrome

Abstract Disclosure: D. Cuevas Ramos: None. G. Garza García: None. W. Hernández Núñez: None. F.J. Gómez Pérez: None. Introduction: Establishing the cause of Cushing’s syndrome remains challenging. Bilateral Inferior Petrosal Sinus Sampling (BIPSS) is the gold standard for distinguishing between Cushing's disease (ACHT-secreting pituitary adenoma) and an ectopic source of ACTH. However, BIPSS is an invasive test and is not widely available. Therefore, we sought to explore the diagnostic efficacy of the 7 mg dexamethasone suppression test (7mg-dexa) for establishing the diagnosis of Cushing's disease (CD). Methods: We reviewed 1375 cases with pituitary adenomas. From them, 191 cases had confirmed diagnosis of CD from 1999 to 2022. Of these, 25 patients underwent 7 mg dexamethasone suppression test together with BIPSS during their diagnosis workup. A diagnosis of CD was established in 21 patients, confirmed after neurosurgery, with a pathology report of ACTH+ secreting pituitary adenoma, and a biochemical resolution of CS. The additional 4 cases showed an adrenal source of CS. Suppression of 50% or more in the afternoon (of day 1 after 7 mg-dexa IV infusion by 7h starting at 7:00 hrs at 1 mg/hr) was considered consistent with CD. A central-to-peripheral plasma ACTH gradient of ≥2 before and after desmopressin stimulation was also considered consistent with CD during the BIPSS. We calculated kappa index to evaluate concordance between diagnostic test. Also, sensitivity (S), specificity (E), positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+) and negative likelihood ratio (LR-) were calculated. Results: The mean age was 43±12.1 years, with a BMI of 30±5.6 kg/m2, 86% females. For the basal ACTH values during BIPSS, the S=76%, E=75%, PPV=94%, NPV=37%, LR+=3, LR-=0.3. For the post-stimulation BIPSS, the S=95%, E=75%, PPV=95%, NPV=75%, LR+=3, LR-=0.06. Using the 7mg-dexa, a S=91%, E=75%, PPV=95%, NPV=60%, LR+=3.6, LR-=0.12. Kappa between test was 0.6 before stimulation, and 0.7 after desmopressin stimulation showing acceptable concordance. Conclusion: The 7 mg-dexa showed similar and acceptable diagnostic performance in comparison with basal or stimulated BIPSS. Since 7mg-dexa inhibition test is less invasive and less expensive, further clinical research to evaluate its utility in CD diagnostic approach is in order. Presentation: Saturday, June 17, 2023

SAT321 Ectopic ACTH Cushing's Syndrome Caused By A Large-cell Neuroendocrine Lung Carcinoma Responding To Desmopressin

Abstract Disclosure: S. Larose: None. D. Rioux: None. R. Albadine: None. A. Lacroix: None. Background: Ectopic ACTH secretion (EAS) is a less frequent cause of ACTH-dependent Cushing’s syndrome (CS), most often caused by a thoracic neuroendocrine tumor (NET). Large-cell neuroendocrine carcinomas (LCNEC) with EAS are rare and usually present a more severe phenotype of ACTH secretion and hypercortisolism. Clinical Case: We report the case of a 44-yo non-smoking man, who presented clinical and biochemical evidence of ACTH-dependent severe CS complicated by pulmonary emboli. In the context of an initial equivocal pituitary MRI, desmopressin and CRH stimulation tests were performed. Desmopressin produced a 157% increase in ACTH (basal: 59.0 pmol/L to peak: 151.9 pmol/L) and a 25% increase in cortisol from baseline; there was no stimulation of ACTH or cortisol during a CRH test and no suppression with high dose dexamethasone tests. Repeat pituitary MRI identified a 5 mm lesion, but inferior petrosal venous sinus sampling (IPSS) under desmopressin did not identify a central ACTH source. Thorax and abdominal imaging including Indium-111 octreoscan identified a left lung 3 mm micronodule which became more evident when pulmonary emboli resolved. In this context of probable ectopic ACTH secretion, the patient was treated with left inferior lung lobectomy for a suspected NET. Pathological studies confirmed a lung LCNEC with morphologic features of carcinoid tumor and strongly positive ACTH immunohistochemistry (IHC) in the primary lesion and lymph node metastasis. The patient was in CS remission after surgery and adjuvant chemotherapy, but developed a CS recurrence 9.5 years later, with a morning ACTH of 56.9 pmol/L, (N <11.0 pmol/L), a non-suppressed AM cortisol of 633 nmol/L after 1mg of dexamethasone overnight and urinary free cortisol of 1717 nmol/24 hours (N:< 789). Imaging showed signs of recurrence, with a hypermetabolic, 14 x 11 mm left hilar lymph node lesion on a TEP-DOTATATE scan in the left lung, near the surgical suture. An endobronchial ultrasound-guided biopsy confirmed the recurrence of the LCNEC. Surgery was performed and demonstrated again positive ACTH IHC of the lesion. The patient achieved remission of CS with secondary adrenal insufficiency, treated with hydrocortisone. Six months later, there was no response of ACTH or cortisol to a desmopressin test. Conclusion: This is the first report of LCNEC with morphologic feature of carcinoid tumor of the lung with ectopic ACTH secretion stimulated by desmopressin. Long delay prior to metastatic recurrence indicates relatively indolent NET. This case report indicates that response to desmopressin can occur in malignant LCNEC. Combining the desmopressin test with other dynamic tests, sellar MRI, IPSS and thoraco-abdominal functional imaging improves diagnostic accuracy of ectopic ACTH source. Presentation: Saturday, June 17, 2023

PMON123 Diagnostically Challenging Case of Cushing's Syndrome from a Pancreatic Neuroendocrine Tumor Treated with Radiofrequency Ablation

Abstract Background The delayed diagnosis of Cushing's syndrome (CS) results in advanced disease, treatment delays and poor outcomes. We present a patient with ectopic ACTH-syndrome (EAS) from a pancreatic neuroendocrine tumor (NET) whose care posed significant diagnostic and therapeutic challenges. Clinical Case 59F with classic Cushing's stigmata (including striae, plethora, supraclavicular and dorsocervical fat pads, muscle wasting), and two-year history of rapid weight gain, hypertension, T2DM, hyperlipidemia, severe osteoporosis complicated by multiple vertebral compression fractures, presented for workup and management of ACTH dependent CS. CS was confirmed (Baseline: ACTH 96 [7.2-63.3 pg/ml], serum cortisol 19.6 [4.8 - 19.5 mcg/dL]; LDSST: cortisol 18.5 [<1.8 mcg/dL], dexamethasone 547 [>200 ng/dL]; 24-hour Urine Free Cortisol: 191.60 [<45 mcg/d], 24-hour Cr 484 mg/day; LNSC: 436, 464 [29-101 ng/dL]; 8 mg ODST cortisol 7.2 mcg/dL). Pituitary MRI showed possible 0.5 cm left anterior pituitary lesion. Inferior petrosal sinus sampling (IPSS) to differentiate between Cushing's disease and EAS was initially planned, however, her course was complicated by an NSTEMI and acute/subacute lacunar infarcts in the left parietal and frontal lobes, and IPSS was deemed contraindicated. Additional workup was pursued including POMC 154 [<40 fmol/ml], Chromogranin A 538 [0-103 ng/ml] (on pantoprazole), pancreatic polypeptide 798 [0 - 435 pg/mL], 24-hour 5HIAA/Creatinine 3 [0 - 15 mg/24hr]. Chest/Abdominal/Pelvis CT showed a 1.5 cm incidental lipid rich adrenal adenoma; workup was negative for pheochromocytoma/ Conn's tumor/ adrenocortical carcinoma. Given elevated POMC and clinical suspicion for EAS, the patient underwent 68Ga-DOTATATE PET-CT scan which revealed an avid 7 mm lesion (SUVmax 14.5) in the pancreatic tail suspicious for a pancreatic NET- the presumed ectopic source of ACTH. Given the patient's poor functional status she was not a candidate for tumoral resection via distal pancreatectomy. Ketoconazole was initiated for treatment of hypercortisolism with good biochemical control, but the patient developed liver toxicity. The decision was made to pursue endoscopic ultrasound guided biopsy and radiofrequency ablation of the lesion. Pathology confirmed ACTH immunoreactive low-grade pancreatic NET. Post-procedure, morning ACTH was 8 pg/ml and cortisol was 9.1 mcg/dL, and the patient required steroids for relative adrenal insufficiency. Further follow up with repeat POMC, cortisol, ACTH levels, 24-hour UFC is required to monitor response. Conclusion IPSS is the gold standard test for differentiating Cushing's disease from EAS but is only available in select centers and for suitable candidates. This case supports the potential utility of POMC peptide measurements in the differential diagnosis of CS and the use of advanced nuclear imaging modalities for tumor localization. For patients with functional pNET who are poor surgical candidates or intolerant of pharmacotherapy, novel endoscopic ablation may offer a lower risk therapeutic option and its use should be further investigated. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Abstract 95: Cushings: The tale of a great mimicker and its conundrums

Background: Cushing's syndrome is a rare endocrine disorder comprising of large group of signs and symptoms resulting from chronic exposure to state of endogenous hypercortisolemia or exogenous steroids. It is a gamut of clinical manifestations with varying presentation and indecisive diagnosis.Aim: We hereby present a case of 28-year-male with signs and symptoms of florid and rapid onset hypercortisolemia of 1 year duration.Objectives and Results/Case Details: Case was referred from psychiatry for weight gain. Clinical history and profound proteo-catabolic signs pointed towards rapid onset cushings. On evaluation hypercortisolism was non-suppressible by 1 mg dexamethasone (DST) and had high ACTH suggesting ectopic ACTH syndrome or pituitary origin. He had a history of watery diarrhea, recalcitrant hypokalemia, multiple hyper-pigmented acne, and striae with secondary superficial mycosis which compelled us to rule out ectopic, but CT chest & abdomen were inconclusive. MRI pituitary showed 4 mm adenoma, cortisol was suppressed following 8 mg DST. He underwent Trans-sphenoidal surgery (TSS), following which cortisol levels normalized within 1week with regression of symptoms.Conclusion: Throughout the course, several diagnoses were entertained like perceptive disorder due to depression and bizarre paresthesia (hypocalcemia), carcinoid syndrome secondary to diarrhea and dys-electrolytemia, ectopic ACTH source due to clinical profile, coincidental lung lesion, but ultimately proven as ACTH producing pituitary tumor out of the blue. Use of a more pragmatic approach makes this case a challenging one.

AACE2021-A-1094: Clinical Profile and Treatment Outcome in Patients with Cushing Syndrome: a 15-Year Experience at a Tertiary Care Hospital in Pakistan

Cushing’s Syndrome (CS) results from chronic exposure of body to excessive production of glucocorticoids. Etiology of CS may lie in the adrenal gland, pituitary gland (Cushing Disease, CD), or ectopic ACTH production by certain malignancies. Surgical excision of culprit lesion remains the most effective procedure. To the best of our knowledge, this important endocrinal entity of CS had never been researched in Pakistan. This descriptive cohort study was conducted at Aga Khan Hospital, Karachi. Data of patients with biochemical and radiological diagnosis of Hypercortisolism presenting between January, 2005 to December, 2019 was reviewed. Patients with history of intake of Glucocorticoids were excluded. Of the 50 subjects, with mean age of 34.72 ± 13.83 years, 33 (66%) were female while 17 (34%) were male.The mean duration of presentation was found to be 1.94 ± 1.83 years after onset of symptoms. Weight gain was the most common presenting complaint. Pituitary lesion was the culprit source in 38 (76%) cases, ectopic ACTH source in 8 (16%) cases and adrenal lesion in only 4 (8%) cases. Among the 38 patients with CD, 30 (79%) underwent TSS and 14 (47%) attained remission. Among the 8 patients with Ectopic ACTH source, only 1 (12.5%) underwent surgical excision and attained remission while 3 patients attained remission with medical treatment only. Out of the 4 patients with Adrenal source, 3 (75%) underwent uni/bilateral adrenalectomy and all (100%) attained remission. Pituitary lesion is the most common source of endogenous hypercortisolism. TSS is followed by a relatively low remission rate of 47% as compared to the developed world.

The value of [68Ga]Ga-DOTA-TATE PET/CT in diagnosis and management of suspected pituitary tumors

BackgroundGallium 68-tetraazacyclododecane-tetraacetic acid-octreotate ([68Ga]Ga-DOTA-TATE) is a selective somatostatin analogue ligand, which shows increased affinity for somatostatin receptor subtype (SSTR) 2 and has been used routinely for imaging neuroendocrine tumors with PET/CT. We investigated the utility of [68Ga]Ga-DOTA-TATE positron emission tomography/computed tomography (PET/CT) in patients with suspected pituitary pathology. We reviewed imaging for twenty consecutive patients (8 men, 12 women, mean age of 48.2, range 14–78) with suspected pituitary pathology who were referred for [68Ga]Ga-DOTA-TATE PET/CT.ResultsNine patients presented with recurrent Cushing’s syndrome following surgical resection of pituitary adenomas due to recurrent Cushing’s disease (seven patients) and ectopic ACTH secreting tumor (2 patients). All seven patients with recurrent Cushing’s disease showed positive pituitary [68Ga]Ga-DOTA-TATE uptake while both cases of ectopic hormonal secretion had absented pituitary uptake. In 1 of these 2 patients, [68Ga]Ga-DOTA-TATE was able to localize the source of ectopic ACTH tumor.Six patients presented de novo with Cushing’s due to ectopic ACTH secretion; [68Ga]Ga-DOTA-TATE PET/CT was able to localize ectopic tumors in six of eight patients (3 lungs, 2 pancreases, 1 mid-gut)There was high uptake [68Ga]Ga-DOTA-TATE in 3 cases of recurrent central hyperthyroidism (SUVmax 6.6–14.3) and 2 cases of prolactinoma (SUVmax 5.5 and 11.3).ConclusionAbsent [68Ga]Ga-DOTA-TATE activity in the pituitary fossa is useful in excluding pituitary disease in recurrent Cushing’s. Recurrent pituitary thyrotropinomas and prolactinomas showed moderate to high pituitary activity. In addition, in Cushing’s syndrome, [68Ga]Ga-DOTA-TATE is useful for detection of ectopic sources of ACTH production, especially where anatomic imaging is negative.

Severe Cyclical Hypercortisolism Due to Metastatic Neuroendocrine Cancer Initially Diagnosed as Colon Cancer

Case Description: A 65 year-old male with initial diagnosis of metastatic colon cancer based on liver biopsy presented for evaluation of severe hypercortisolism with 24-hour urinary free cortisol (UFC) of 1184 mcg/day after presenting to his Oncologist in December 2019 requesting evaluation for muscle weakness and weight gain. On re-evaluation in March, his cortisol had dramatically improved with 24-hr UFC of 120 mcg/day and ACTH of 84 pg/mL and had resolved with 24-hr UFC of 32.6 mcg/day by May.A 2 cm pancreatic lesion was noted during cancer staging; a second opinion was obtained on the liver biopsy which was interpreted as metastatic neuroendocrine tumor, possibly of pancreatic origin. The patient was started on FOLFINIRNOX in December 2019. This was transitioned to carboplatin and etoposide after the revised diagnosis and was continued through May with regression of liver lesions on followup imaging. A 68 Ga-DOTATATE PET CT confirmed uptake in the pancreas, retroperitoneal lymph nodes, and thyroid. A thyroid ultrasound was obtained which did not meet FNA criteria.Given the chronologic association between cortisol levels and chemotherapy response we were suspicious for ectopic Cushing’s syndrome due to metastatic neuroendocrine cancer and the patient was followed for recurrence. In September, the patient endorsed leg weakness and hyperglycemia and was found to have a 24-hr UFC of 4731 mcg/day and an 8 am cortisol of 102 mcg/dL.The patient developed severe hypokalemia requiring admission and was restarted on chemotherapy with moderate improvement in cortisol levels and symptoms. Given the degree of cortisol elevation, we recommended bilateral adrenalectomy, for which the patient established care at a more specialized center.Discussion: Ectopic Cushing’s syndrome is an uncommon variety of ACTH-dependent Cushing’s syndrome caused by CRH or ACTH-producing tumors. The more aggressive form is associated with small-cell lung cancer while the chronic form is associated with indolent tumors.Cyclical Cushing’s syndrome is a rare cause of hypercortisolism characterized by cyclical variations in cortisol levels. The pathophysiology of the cyclical variation is unclear. About half of cases are caused by pituitary corticotrophs but up to 26% can be attributed to ectopic ACTH production, typically due to indolent tumors rather than aggressive malignancies.We present a case of cyclical hypercortisolism with an initial diagnosis of colon cancer. On further review, the cyclical hypercortisolism was likely associated with chemotherapy response. Reevaluation of surgical pathology was consistent with metastatic neuroendocrine cancer, the likely source of ectopic ACTH.Our case highlights the importance of maintaining a broad differential when considering cases of cyclical cortisol elevation, including consideration of concurrent chemotherapy for seemingly unrelated malignancies.

ACTH-Dependent Cushing’s Syndrome in an Elderly Woman with Pituitary, Adrenal, and Intrathoracic Lesions

A 77-year-old female with rheumatoid arthritis on etanercept, depression on venlafaxine, and treated hypothyroidism presented with easy bruising and muscle weakness. She denied any steroid use. She had normal BP and BMI, but appeared mildly Cushingoid with round facies, and increased dorsocervical and supraclavicular fat.Laboratory evaluation showed: ACTH 70.8 pg/mL (< 63.3), cortisol 24.3 ug/dL, 24 h urine free cortisol 223 ug (< 50), salivary cortisol 0.428 ug/dL, DHEA-S 165.7 ug/dL (< 142.8), LH 0.1 mIU/mL, FSH 2.7 mIU/mL, and hgbA1C 6.1 % (< 5.6 %). All other hormonal testing was normal. MRI of the pituitary showed a 4 x 2 x 3 mm hypoenhancing defect of the anterior pituitary. CT of the chest and abdomen showed a 1.1 cm left adrenal nodule, and a 1 cm non-specific right middle lobe lung nodule. Inferior petrosal sinus sampling (IPSS) with CRH did not show a central ACTH step-up. PET/CT with DOTATATE showed mildly increased tracer uptake in the right middle lobe measuring 1 cm with SUV max 3.7, and a 0.6 cm left apical subpleural nodule with SUV max 1.9.The patient underwent a right middle lobectomy and pathology was positive for typical carcinoid. Post-operatively, she needed hydrocortisone replacement for 9 months. ACTH was 19.7 pg/dL, cortisol 9.5 ug/dL, DHEA-S 31.3 ug/dL, LH 61.8 mIU/mL, and FSH 112.4 mIU/mL. Her Cushingoid features and myopathy resolved.This case highlights several challenges in the diagnosis and source localization in patients with ACTH-dependent Cushing’s Syndrome (CS). In this slim, elderly female, the typical features of CS were subtle. In addition, dynamic biochemical testing with high dose dexamethasone does not reliably distinguish eutopic from ectopic ACTH-dependent CS, as the sensitivity and specificity range from 60–80%. Thus, the diagnosis largely depends on sophisticated imaging and IPSS.The patient had pituitary, adrenal, and lung lesions. The pituitary lesion initially pointed towards a central ACTH source, but IPSS was negative. The prevalence of pituitary incidentalomas is high, at 10.6% based on autopsy data, with an increasing proportion being recognized in the elderly. Adrenal incidentalomas are also often noted in older individuals, but that was clearly not the cause of CS in this patient with a non-suppressed DHEA-S and elevated ACTH. PET/CT with DOTATATE has emerged as a sensitive test for the detection of often small tumors producing ectopic ACTH and was positive in the lung lesion. In spite of newer localization techniques, the source of ectopic ACTH often remains unidentified (12.5% in a large retrospective case-record study). False negatives on PET/CT with DOTATATE imaging may be due to cortisol’s suppressive effect on the somatostatin receptor expression in neuroendocrine tumors. Thus, in cases of ACTH-dependent CS with negative IPSS, ectopic ACTH must remain as a likely source, and be re-explored after medical treatment of the hypercortisolism.

Severe Cushing Syndrome Due to Ectopic ACTH Secretion by Pheochromocytoma

Introduction: Ectopic ACTH production is a very unusual cause of Cushing Syndrome (CS). When it occurs, lung cancer is the main cause. Very rarely, this ectopic source of ACTH can arise from a Pheochromocytoma (Pheo). A recent literature review identified less than 100 cases described. We present a case of 28 years old woman who was referred for adrenalectomy for CS with notorious adrenal mass. However, during the investigation, ectopic ACTH due a Pheo was identified. Case Report: A 28-year-old woman required emergency care for ecchymosis and asymptomatic hypertension (BP: 230x130mmHg). Hyperpigmentation of the skin was evident on physical examination. Severe hypokalemia (K: 2.5mEq/liter) was detected. She denied taking any medication and was unaware of any previous illness. She always had normal BP measurements as well as laboratory tests. No family history of adrenal disease or secondary hypertension causes. During hospitalization, the hypothesis of CS was made and confirmed after: cortisol after 1mg dexamethasone: 44.5mcg/dl (<1.8mcg/dl) and 24h urinary free cortisol: 6228 mcg/dl (28-213mcg/dl). Concomitantly, a CT scan of the abdomen exhibited a left adrenal mass (3.1x2.8x3.5cm) of uncertain etiology and ACTH: 352pg/ml (<46pg/ml). Additionally, the patient presented hyperglycemia during hospitalization. After confirmation of the ACTH dependent CS, pituitary MRI was performed with normal results and a chest CT scan ruled out lung masses. As there was still no etiological confirmation and due to clinical deterioration, it was decided to start Ketoconazole 200mg/day, rising until 600mg and spironolactone with doses up to 250mg/day with a significant improvement in hypokalemia, decreased cortisol levels and optimal BP control. Due to the extremely high levels of ACTH and indeterminate adrenal mass, the hypothesis of ACTH ectopic due Pheo was postulated. Patient underwent abdomen MRI with left adrenal mass with hypersignal at T2 and urinary metanephrines levels: 6132mcg/24h (<289mcg/24h), urinary normetanephrines: 1808mcg/24h (<732mcg/24h). Once the diagnosis was elucidated, she received preoperative preparation with alpha blocker (Doxazosin) and underwent adrenalectomy without complications. After discharge, she received prednisone 10mg/day. The patient presented normalization of BP levels, as well as glycemic control with a slight improvement in skin hyperpigmentation. The pathology department confirmed Pheo and an ACTH expression was observed in immunohistochemistry. A genetic panel for Pheo is running with no results so far. Conclusion: Despite an extremely rare cause of CS, the ectopic production of ACTH by a Pheo has extremely high mortality rates, especially when not diagnosed or managed correctly. The clinicians must always remain alert and suspect this syndrome when the patient has a confirmed ACTH dependent CS associated with adrenal masses.

MON-329 Diagnostic Utility of Overnight High Dose Dexamethasone Suppression Test for Differentiating the Etiology of ACTH Dependent Cushing’s Syndrome

Background:Bilateral inferior petrosal sinus sampling (BIPSS) has been the gold standard in differentiating a pituitary vs. an ectopic source of ACTH in Cushing’s syndrome however, it has many limitations. The ON-HDDST being simple to perform and the tests of choice in resource poor setting. The primary aim of our study was to consolidate the present knowledge regarding the diagnostic utility of ON-HDDST in localizing the source of ACTH.Method:We retrospectively studied 88 patients with ACTH dependent Cushing syndrome who underwent ONHDDST. Patient were considered as Cushing disease (CD) if either of the 3 criteria were met a) histopathological confirmed b) a central to peripheral gradient >2 was seen in BIPSS or c) pituitary adenoma ≥ 6mm seen in MRI of pituitary. Patient were considered as ectopic ACTH syndrome if the tumor was localized at any peripheral location by imaging or histopathological confirmed after surgery or if BIPSS shown a central to peripheral gradient of <2. Result: Out of total 88 ACTH dependent Cushing syndrome patients, 68 (77.3%) were proven CD and 20 (22.7%) were ectopic. There was no difference in basal serum cortisol however, S. Cortisol after ONHDDST was significantly different between the two with a median of 547.7 nmol/l (341-770) in ectopic vs 273.5 nmol/l (142-689) in CD (p=0.02). A positive response to ONHDDST (≥50% suppression) was seen in about 44 (65%) patients with CD and 5 (25%) patients with ectopic disease (p = 0.002). Among CD patient, 35 (76.1%) of those with microadenoma, 7 (43.8%) amongst macroadenoma and 2 (33%) patient with no visible tumor on MRI shown positive response to ONHDDST. In ectopic group, cortisol suppressibility was seen in 3 (50%) patient with occult tumor but only in 2(14.3%) patient with. ROC curve plotted for percentage suppression of cortisol after ONHDDST shown as AUC equal to 0.68 (p = 0.01). The best test parameters with sensitivity (65%), specificity (85%) and Accuracy (69%) were seen at 50% cutoff level as were the likelihood ratio for positive test (4.3), AUC (0.75), PPV (93.6%), NPV (41.4%). Conclusion: Our study has shown that ONHDDST has poor diagnostic value in differentiating between CD and ectopic ACTH syndrome whatever be the cutoff level of the cortisol suppression. However, this can still be utilized in setups where no alternative is available. For etiologic confirmation, another test with better sensitivity and specificity is preferable.

SAT-127 Localization and Treatment of the Ectopic ACTH Syndrome Using Somatostatin Analogues

Ectopic ACTH syndrome (EAS) is a rare disorder with a high morbidity and mortality due to the sequelae of severe hypercortisolism and possible underlying carcinoma. It is caused by various tumors, some originating from neuroendocrine cells. Optimal management includes localization and removal of the ectopic ACTH source. About 80% of these tumors have somatostatin (SS) receptors, so that SS analogues may be useful in the localization and treatment. This case demonstrates the use of SS analogues in localization and treatment of EAS.A 49-year-old female presented with 7 months of worsening Cushingoid features including rounded plethoric face, full supraclavicular fat pads, facial hair growth, multiple bruises, violaceous abdominal striae, kyphoscoliosis, 4+ peripheral edema, weight gain, hypertension (190/110 mmHg) and thoracic compression fractures. AM plasma ACTH concentration was 333 pg/mL (nl = 6 - 58 pg/mL); serum concentration cortisol was 71.4 mcg/dL (nl = 7 - 23 mcg/dL) and serum potassium concentration was 1.2 mmol/L (nl = 3.6 - 5.1 mmol/L). A 24-hour urine cortisol could not accurately be obtained. High dose 8 mg overnight dexamethasone testing demonstrated suppression of serum cortisol concentration from 71.4 to 6.3 mcg/dL, suggesting pituitary Cushing disease. Pituitary MRI scan revealed a 2.5 mm disc shaped cystic focus suggesting a Rathke’s cleft cyst. No central-to-peripheral ACTH gradient was present on bilateral inferior petrosal sinus sampling suggesting an ectopic ACTH source. There was a 1.2 x 1.0 cm nodule in the left lower lung lobe on CT chest. A gallium-68 dotatate PET/CT scan demonstrated enhancement of this same lung lesion and mild uptake in the left inferior hilum, suggesting a neuroendocrine lung tumor with possible metastases to lymph nodes. Biopsy and resection of the lesion was deferred until after control of her hypercortisolism. 30mg of Sandostatin LAR was started every 4 weeks to control the ectopic ACTH secretion and to confirm that the SS analogue positive lung lesion was the cause of the EAS. Sandsostatin LAR therapy over the next 12 weeks resulted in a steady clinical and biochemical improvement with a decrease in serum cortisol to 9.7 mcg/dL, control of hypertension (108/64 mmHg), weight loss of 6 pounds, and resolution of supraclavicular fat pads, hypokalemia, and peripheral edema. This confirmed our impression that the neuroendocrine lung tumor was the ACTH source.In summary, this patient with EAS had severe clinical manifestations of hypercortisolism and could not safely undergo surgical intervention. This case demonstrates the value of SS analogues (gallium-68 dotatate PET/CT and Sandostatin LAR) in localizing and confirming the source of ectopic ACTH production and markedly improving the clinical and biochemical features of the EAS.

SAT-LB52 A Case of Cushing’s Syndrome in a Patient With Addison’s Disease

This is a case of a 56-year-old female with history of Addison’s disease, T1DM, hypothyroidism and Asthma. She was diagnosed with Addison’s disease after multiple hospital visits consistent with adrenal crises (Fatigue, weakness, salt craving, abdominal pain, hypotension, hyperpigmentation and hyponatremia). Multiple abdominal images including CT abdomen did not reveal any pathology. A random cortisol and ACTH were found to be abnormal at 0.5 and 3362, respectively. She was started on Hydrocortisone 10mg in the morning and 5mg in the evening. Her physical exam revealed diffuse hyperpigmentation including palmar creases and oral mucosa. There was no facial plethora or striae. She had no history of proximal myopathy, easy bruising, hypertension or osteoporosis. Upon follow up, exam revealed progressive worsening of her diffuse hyperpigmentation. A random cortisol and ACTH, without holding her Hydrocortisone, revealed 64.3 and >2000, respectively. Concern arose for the possibility for a pituitary corticotrophin adenoma or ectopic secretion of ACTH driving her hyperpigmentation. MRI showed the pituitary gland had normal appearances. As there is a positive correlation between basal plasma ACTH values and the size of the pituitary adenoma in patients with Cushing’s disease the differential of a pituitary corticotrophin adenoma was originally thought to be dropped lower on the list of differentials. Further workup was pursued with an 8mg Dexamethasone suppression test to take advantage of the fact that ACTH secretion by the pituitary adenomas in Cushing’s disease are only relatively resistant to negative feedback regulation by glucocorticoids while most ectopic ACTH production from non-pituitary tumors are completely resistant to feedback inhibition. ACTH levels went from >2000 down to 29 post 8mg Dexamethasone, which led to decreasing suspicion of an ectopic source of ACTH and further concern for a pituitary corticotrophin adenoma in addition to Addison’s disease. ACTH measurements are not widely used in documenting the adequacy of treatment of primary adrenocortical disease. The hormone is released in pulses, particularly in the early hours of the morning, and measurement of isolated samples is of limited value. Inappropriately normal to slightly elevated ACTH levels despite adequate glucocorticoid replacement in patient with adrenal insufficiency could be related to an altered pituitary sensitivity to cortisol suppression. Extremely elevated ACTH levels despite supra-physiological glucocorticoid replacement in a patient with Addison’s raises the question as to what is the source of ACTH?

SAT-146 A Rare Combination of Severe Ectopic Cushing’s Syndrome and Graves Hyperthyroidism: A Case Report

BACKGROUND: Ectopic ACTH secretion (EAS) is a rare cause of Cushing’s syndrome. Olfactory neuroblastoma (ONB) is a malignant tumor derived from the olfactory epithelium and can rarely be a source of ectopic hormone production. There are only 19 reported cases of EAS from ONB. We report a case of severe ectopic Cushing’s due to ONB. Interestingly, the patient also presented with Graves disease, which is an unusual pathophysiologic combination since supraphysiologic levels of glucocorticoids suppress the immune system, thereby ameliorating autoimmune processes. Remarkably, Graves disease improved following the removal of the source of ectopic ACTH. CASE PRESENTATION: A 41year old male presented with epistaxis, anosmia, and headaches. He also reported recent weight gain, muscle weakness, and new onset hypertension. Cross-sectional imaging revealed a right nasal cavity mass with intracranial extension. Endonasal biopsy was consistent with a diagnosis of ONB. Biochemical evaluation demonstrated hypokalemic alkalosis, hyperglycemia, and severe hypercortisolism [ACTH 734 (9-46 pg/ml), am cortisol 110 (2-15 ug/ml), late night salivary cortisol 9.8 and 22.53 (<0.09 ug/dl), 24 hour UFC 41,337.3 (4-50 mcg) and non-suppressed cortisol 110 (1.8 mcg/dl) by 1 mg dexamethasone]. Pituitary MRI showed no sellar pathology. Following a period of cortisol suppression with Ketoconazole then with Etomidate infusion, the patient underwent resection of the ONB, followed by chemo- and radiotherapy, which resulted in improvement of severe hypercortisolism. Histopathology showed positive ACTH immunostaining. Pre-operative evaluation also demonstrated hyperthyroidism: TSH <0.010 (0.3-5uIu/ml), FT4 3.11 (0.89-1.76 ng/dl), normal TT3 0.81 (0.6-1.81 ng/ml). Thyroid auto-antibodies were negative; however, radioiodine scan and uptake demonstrated diffusely increased uptake in the enlarged thyroid gland. Pre-operative euthyroidism was achieved with a combination of methimazole, SSKI and cholestyramine. After 6 months of methimazole therapy the patient presented with hypothyroidism (TSH 72.37, FT4 0.1). Methimazole was discontinued and he achieved euthyroidism on subsequent evaluations. CONCLUSION: EAS due to ONB is a very rare cause of Cushing’s syndrome. To our knowledge, this is the first reported case of a male presenting with EAS and concurrent Graves hyperthyroidism. An extensive review of the literature and seeking expert opinion did not provide a convincing pathophysiologic explanation to this unusual concurrence. We therefore hypothesize that, while the two endocrine conditions were simultaneous, they were likely unrelated.

Pulmonary embolism as the presenting symptom and a confounder in ACTH-secreting bronchial carcinoid

SummaryEctopic ACTH-secreting pulmonary neuroendocrine tumors are rare and account for less than 5% of endogenous Cushing’s syndrome cases. We describe an unusual case of metastatic bronchial carcinoid tumor in a young woman presenting with unprovoked pulmonary emboli, which initially prevented the detection of the primary tumor on imaging. The source of ectopic ACTH was ultimately localized by a Gallium-DOTATATE scan, which demonstrated increased tracer uptake in a right middle lobe lung nodule and multiple liver nodules. The histological diagnosis was established based on a core biopsy of a hepatic lesion and the patient was started on a glucocorticoid receptor antagonist and a somatostatin analog. This case illustrates that hypercogulability can further aggravate the diagnostic challenges in ectopic ACTH syndrome. We discuss the literature on the current diagnosis and management strategies for ectopic ACTH syndrome.Learning points:In a young patient with concurrent hypokalemia and uncontrolled hypertension on multiple antihypertensive agents, secondary causes of hypertension should be evaluated.Patients with Cushing’s syndrome can develop an acquired hypercoagulable state leading to spontaneous and postoperative venous thromboembolism.Pulmonary emboli may complicate the imaging of the bronchial carcinoid tumor in ectopic ACTH syndrome.Imaging with Gallium-68 DOTATATE PET/CT scan has the highest sensitivity and specificity in detecting ectopic ACTH-secreting tumors.A combination of various noninvasive biochemical tests can enhance the diagnostic accuracy in differentiating Cushing’s disease from ectopic ACTH syndrome provided they have concordant results. Bilateral inferior petrosal sinus sampling remains the gold standard.

SUN-368 Fatty Hypertrophy of the Hip as a Clinical Manifestation of Cushing Syndrome

Background: Increased fat deposition is a hallmark of exogenous and endogenous hypercortisolism (Cushing’s syndrome, CS). Fat accumulates not only in the abdomen and liver, but also in unusual locations such as the temporal and supraclavicular fossae, intrascapular fat pads and spinal epidural space (1). Here we describe, to our knowledge, the first report of intracapsular fat deposition at the hip in a patient (pt) with CS. Case Presentation: A 47 year old African American male presented with a six year history of diabetes and hypertension. He also reported abdominal weight gain, moodiness, facial flushing, blurry vision, fatigue, joint aches (especially knee and hips), muscle weakness leading to falls, difficulty with ambulation, straie, and decreased memory. Physical exam on admission revealed a rounded face with bitemporal fat pads, supraclavicular and dorsocervical fat pads, central obesity, +1 pitting edema of the lower extremities, 4/5 strength in shoulders and hips, ankle flexion and hand grip strength 5/5, wide violaceous striae on the abdomen. Biochemical evaluation revealed urine free cortisol 1460.8 and 1031.2 mcg/24h (ref: 3.5-45 mcg/24h), and plasma ACTH levels of 51.3-158 pg/ml (ref:5-46pg/ml). Pituitary MRI showed an 8mm lesion, CRH stimulation test showed 52% increase in cortisol level (29.8 to 43.1 mcg/dl) and a 79% increase in ACTH level, (95.9 to 175 pg/ml), suggestive of Cushing’s disease. However, cortisol increased by 41% after 8mg dexamethasone (23.2 to 32.8 mcg/dL), and IPSS also was consistent with an ectopic source of ACTH. A 10mm right hilar lesion was identified by CT, MRI, and 68Ga-DOTATATE. While awaiting surgical resection, pt was treated with ketoconazole and metyrapone. Three weeks after initiation of medical therapy, pt reported new unprovoked bilateral hip pain with antalgic gait. MRI hip revealed only bilateral symmetric intracapsular fat abutting the superolateral aspects of the femur in the subcapital region. There was no evidence of avascular necrosis of bone, osteoarthritis, or collagen tear. Physiatry evaluation reported functional hip strength in the 4- range, hip extension bilaterally 2+, unchanged ability from a prior admission to stand from sitting position without the use of upper extremities, and ability to ambulate independently across a room, but necessary use of a single point cane for longer distances. Physical therapy noted a decline in his mobility status since last visit, and recommended use of a wheeled walker. Discussion: This is the first time we have identified a patient with increased fat in the hip joint explained by no other comorbidities other than Cushing’s Syndrome. This new finding adds another unusual location for increased adipose in the clinical presentation of patients with CS. Further studies are needed to better assess the correlation between the finding of intracapsular hip fat, pain and hypercortisolism.

MON-409 Ectopic ACTH Syndrome with a Pituitary Mass

Background: The ectopic ACTH syndrome comprises 10% of Cushing’s syndrome cases. It is associated with an array of both highly malignant and more indolent tumors. Clinical features develop rapidly in ectopic ACTH syndrome. Distinguishing ectopic ACTH production from pituitary ACTH secretion is essential in determining appropriate management and may be challenging in the case of an occult neuroendocrine tumor. Clinical Case: A 46 year-old male presented to the ER after his PCP identified hypokalemia to 1.6 mmol/L (3.5- 5.0 mmol/L). He endorsed two weeks of proximal muscle weakness, lower extremity edema, a retro-orbital headache, and 10lb weight loss. Exam revealed mild facial fullness and pitting edema to the knees. No supraclavicular or dorsal cervical adiposity, violaceous abdominal striae or hyperpigmentation was observed. His blood pressure was elevated at 177/92 and an EKG revealed sinus bradycardia at a rate of 44 bpm. An 8AM cortisol was elevated at 67.4 mcg/dL (2.5-19.5 mcg/dL). ICU admission for blood pressure control and IV potassium supplementation was required. There was concern for Cushing’s disease given an inappropriately elevated ACTH level of 159.3 pg/mL (6-50 pg/mL). However, ectopic ACTH was highly suspected given the rapid development of symptoms and a smoking history of roughly 60 pack yrs. A CT of the chest, abdomen, and pelvis revealed no findings suspicious for malignancy. An MRI brain revealed a 19mm sellar and suprasellar mass atop the pituitary extending superiorly in the supra-diaphragmatic region adjacent to the pituitary stalk with a thickened, enhancing infundibulum. The patient required 60meq TID of oral KCl at discharge. Insulin dependent DMII rapidly developed in the weeks following discharge. An 8mg dexamethasone suppression test was performed with a baseline 8AM cortisol of 88 mcg/dL. Post dexamethasone, 8AM cortisol was 62 mcg/dL. Although these results were not consistent with the 50% reduction in cortisol levels expected by a pituitary adenoma in response to high dose dexamethasone administration, a trans-sphenoidal hypophysectomy was undertaken per patient preference. A pale discohesive tissue was identified intra-operatively which stained for ACTH, consistent with a corticotroph macroadenoma. An Indium-111 pentetreotide scan was negative for evidence of a somatostatin receptor expressing neoplasm. Two months after surgery, early-afternoon cortisol decreased to 7.5 mcg/dL. The patient’s insulin dependence gradually resolved as did his hypokalemia, edema, weakness, and weight loss. Conclusion: We describe an unusual case wherein clinical features of the ectopic ACTH syndrome developed over the course of two weeks in a lifelong smoker. Despite failing an 8mg dexamethasone test, a corticotroph macroadenoma was discovered. There was no identifiable source of ectopic ACTH on an octreotide scan despite a highly suggestible presentation.

MON-318 Selective ACTH Sampling in Localizing Source of ACTH in Von Hippel Lindau Disease with Pancreatic Neuroendocrine Tumour and Renal Cell Carcinoma

Background: Cushing’s syndrome (CS) in a patient with VHL has been attributed to a number of possible causes; pancreatic NET and renal cell carcinoma. The precise location of ectopic ACTH aid enormously in the management of VHL. Clinical case: A 31-year-old woman with Type 2 diabetes and family history of VHL presented with florid features of CS in her second trimester of pregnancy. A diagnosis of ACTH dependent CS was made based on elevated 24h urinary cortisol (1122 and 2448nmol/24hr, n<150-800), midnight cortisol (1322nmol/L, n<220nmol/L) and a detectable ACTH level (18.8pg/mL, n<10pg/mL). She underwent emergency caesarean section due to pre-eclampsia at 28 week gestation. Post-delivery, her morning cortisol was 2823nmol/L (n:171-536nmol/L). MRI pituitary was reported as normal. CT abdomen showed an enlarged pancreas which was almost completely cystic and a right renal mass (3.7 X 2.6 X 4cm). Serum chromogranin A was elevated (530.2ng/mL, n:27-94). 24h urinary free metanephrine was normal. Selective ACTH sampling was done together with bilateral inferior petrosal sinus sampling to elicit source of ACTH. Increased gradient of ACTH level compared to the periphery (138.9pg/mL vs. samples from IVC:115.1 pg/mL, renal vein:100.2 pg/mL) was detected from the hepatic vein that drains the pancreas via the portal venous system. Ketoconazole and metyrapone were given to control the cortisol level close to 600nmol/L prior to surgery. Preoperatively, IV hydrocortisone 100mg was administered, with additional 50mg given every 4 hours intraoperatively. Total pancreatectomy and right nephrectomy were performed. Inotropic support was required five hours into the surgery. Hydrocortisone was tapered down to a maintenance dose of 10mg, 5mg and 2.5mg TDS over 7 days. A week after surgery, am cortisol was 103nmol/L suggesting successful removal of ectopic ACTH source. Histopathological examination identified a solid tumour (18X12X12 mm) at the pancreatic tail which stained positive to Chromogranin A, synaptophysin and weakly positive to CD56. The mitoses was 0-1/10hpf with a Ki67 index of 2%. ACTH staining was positive. The renal mass was a Grade 1 clear cell renal cell carcinoma with equivocal ACTH staining. Two months later, there was resolution of cushingoid features. DOTATE and FDG/PET scans along with close surveillance using serum Chromogranin A and 6 monthly abdominal imaging were planned. Conclusion: When managing VHL with CS, there is always a possibility of more than one source of ACTH production. In delineating the cause of CS the use of selective ACTH sampling may be considered where functional imaging (DOTATATE) is unavailable. Reference : (1) Tamura K, Nishimori I, Ito T, Yamasaki I, Igarashi H, Shuin T. Diagnosis and management of pancreatic neuroendocrine tumor in von hippel-lindau disease. World J Gastroenterol. 2010;16(36):4515-4518. doi:10.3748/wjg.v16.i36.4515

Root cause analysis of diagnostic and surgical failures in the treatment of suspected Cushing’s disease

Cushing’s disease (CD) is a condition characterized by excess glucocorticoid from an ACTH pituitary adenoma. Identifying surgical candidates represents a major diagnostic challenge. We performed a root cause analysis (RCA) of treatment failures for patients with suspected CD. The present study aims to categorize failures in treatment. Medical records were reviewed from 2008 to 2017 for all patients treated surgically for suspected CD. Demographics, past medical history, endocrine outcomes, imaging findings, laboratory studies and clinical features were collected. Eighty-five patients were identified with pre-operative suspicion for CD. Thirty-four (40.0%) had undergone prior surgery confirming ACTH adenoma, leaving 51 (60.0%) for analysis. The average length of follow-up was 18.3 ± 24.1 months, 42 (82.4%) patients had postoperative biochemical remission of hypercortisolism. Forty-three (84.3%) had histologically confirmed CD, two (3.9%) were diagnosed with extracranial ACTH-secreting tumors, four (7.8%) had no obvious tumor upon intraoperative exploration, one (1.9%) had suspected pituitary ACTH hyperplasia, and one (1.9%) had no identifiable pathologic tissue despite apparent gross tumor observed during surgery. Thirty-four (66.7%) patients had remission following surgery alone, four (7.8%) after reoperation, and four (7.81%) after radiosurgery. One patient (1.9%) was found to have an ectopic source of ACTH, and one (1.9%) had immunohistochemically confirmed adrenal tumors. On RCA, we identified six categories of treatment failures. CD is a diagnostic challenge that can be difficult to distinguish from other forms of hypercortisolism. Surgical efficacy can be improved with more accurate patient selection, and perhaps with improved imaging methods.

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.

Le syndrome de Cushing paranéoplasique, un vrai défi diagnostique et thérapeutique : à propos d’un cas et revue de la littérature

IntroductionParaneoplastic Cushing's syndrome is a rare cause of endogenous hypercortisolism attributable to ectopic ACTH secretion by non-pituitary tumors. Imaging and biochemical results are often inconclusive and differential diagnosis with Cushing's disease can then be challenging. Moreover, these tumors may be occult and difficult to find and thus the need of new imaging tools such as 18FDG-PET scan and 18DOPA-PET scan. Case reportWe report a 50-year-old man who presented with very aggressive clinical features related to Cushing's syndrome. Biological work-up confirmed the hypercortisolism and was consistent with an ectopic ACTH secretion. Conventional localization techniques failed to show any tumor and bilateral adrenalectomy was performed because of life-threatening complications. Two years later, thoracic computed tomography reveals an 11 mm mass in the left lower pulmonary lobe, 18FDG-PET scan found a non-specific mild hypermetabolism of the lung nodule, and the 18DOPA-PET scan confirmed the high uptake of this nodule suggesting an endocrine carcinoma. Histology confirmed a typical carcinoid tumor. The tumor cells stained positive for ACTH, CD56, chromogranin and synaptophysin. ConclusionThis case illustrates the dilemma between the need for morphological diagnosis of the ectopic ACTH source and control of the life-threatening hypercortisolism. 18FDG-PET scan and 18DOPA-PET scan should be considered early as a secondary diagnostic tool when conventional imagery fails to show any tumor.