Ectopic ACTH-secreting Tumors Research Articles

#2026 Hypokalemia associated to neuroendocrine carcinoma of the cervix

Abstract Background and Aims Hypokalemia is one of the most common electrolyte disorders seen in clinical practice. Hypokalemia can be caused by decreased intake of potassium, redistribution of potassium (K+) in cells or by excessive gastrointestinal losses or renal losses. In this setting, hypokalemia may also be caused by the paraneoplastic production of ectopic adrenocorticotropic hormone (ACTH) by some tumors. Cancer of the uterine cervix is the fourth common cancer affecting women worldwide and the fourth most common gynecologic cancer in Spain. Neuroendocrine carcinoma of the cervix represents about 2% of all cervical neoplasms. Method We report the case of a 44-year-old Peruvian woman with hypokalemia who was diagnosed with Cushing syndrome secondary to paraneoplastic production of ACTH by neuroendocrine carcinoma of cervix. Results Patient was overweight and affected by uterine myoma and anemia without further investigations. She was admitted to our hospital due to lower back pain, leg swelling and constipation. Blood pressure was normal, chest radiography did not show abnormal findings and ECG showed the U wave. Laboratory tests at admission revealed hypokalemia (2.3 mmol/L), metabolic alkalosis, anemia (hemoglobin 9.5 g/dL), hyperkaliuria (K+ urine/Creatinine urine 70 mmol/g) with an elevated transtubular potassium gradient (TTKG=12) and normal renal function. Laboratory data are presented in Table 1. She developed hypertension in the first day of hospitalization. Renin, aldosterone and cortisol tests was performed. Hypercortisolism was observed and confirmed with 24-hour urinary cortisol excretion. Because of an elevated ACTH (263 pg/mL), pituitary magnetic resonance imaging was performed without lesions. Whole-body computed tomography revealed a cervical mass. PET scan showed pelvic, adrenal, hepatic and local lymphadenopathy activity (see Fig. 1). After the histopathological study, diagnostic of small cell neuroendocrine carcinoma of the cervix was made. Chemotherapy therapy was initiated with cisplatin/etoposide regimen. The patient decide to return to Peru because of the poor prognosis of her illness. At discharge, potassium level was 3 mmol/L despite the treatment with spironolactone, ramipril, losartan and oral potassium chloride (160 mmol). Conclusion Hypokalemia is a common clinical disorder. In some patients it may be caused by an increased mineralocorticoid activity due to ectopic ACTH-secreting tumors. Applying diagnostic algorithms to electrolyte disorders, beyond their simple treatment, can unmask secondary causes and serious diseases.

THU527 Metastatic Adenocarcinoma Of The Colon Concealing An ACTH Secreting Neuroendocrine Differentiated Cluster: A Lethal Zebra Within A Trojan Horse

Abstract Disclosure: M. Velasquez: None. S. Shekhar: None. R.M. Goyal: None. Background: Ectopic ACTH secreting tumors are responsible for almost 10% of all cases of Cushing Syndrome. Tumors associated with this entity are most commonly small cell lung, thymic, and pancreatic neuroendocrine tumors. Few cases of colon adenocarcinoma with paraneoplastic ACTH secretion have been reported. They are associated with poor outcomes. Clinical case: A 57-year-old previously healthy male presented with shortness of breath and hypertension. CTA of the chest revealed metastatic liver lesions. CT abdomen and pelvis confirmed metastatic liver lesions with an apple core colonic mass consistent with a primary malignancy. Liver biopsy showed well-differentiated neuroendocrine tumor; tumor cells were negative for CK20, chromogranin, and CD56 but positive for CK7 and synaptophysin. The Ki-67 index was 30%. He was not evaluated for paraneoplastic hormonal secretion and the colonic mass wasn’t biopsied at that time. Ga-DOTATATE scan was negative for somatostatin uptake. He was started on carboplatin-etoposide + dexamethasone (three doses of 4mg each). Two months later presented with large bowel obstruction. Colonoscopy was performed and histopathology demonstrated colonic adenocarcinoma with focal neuroendocrine differentiation with positive CDX2 and negative CK7 and CK20. Synaptophysin was diffusely positive with sparse chromogranin positivity. ACTH stain of the colonic biopsy was negative. Chemotherapy was switched to FOLFORINOX and dexamethasone (one dose of 12mg). After two weeks of being on this regimen, he developed refractory hypokalemia and metabolic alkalosis and was sent to the emergency department. Vitals signs were within normal limits except for mildly elevated blood pressure. Physical examination remarkable for redness of his truncal skin. He did have changes in his handwriting, 0/3 three-word recall, and reduced short term memory. Primary team performed a morning cortisol that was elevated, and endocrinology was consulted. Two repeated 8AM cortisol level and a serum ACTH were found to be elevated. An 8mg overnight dexamethasone suppression test revealed an increase in cortisol. MRI brain showed no evidence of intracranial abnormalities. Refractory hypokalemia due to ectopic ACTH-dependent Cushing syndrome was diagnosed warranting treatment with ketoconazole. Unfortunately, he developed septic shock which led to his demise. Conclusion: This case illustrates a paradoxical rise in serum cortisol levels after dexamethasone suppression test suggesting the presence of positive feedback effects of exogenous corticosteroids on tumor’s ACTH release/production. Recognition of this syndrome is critical to avoid unnecessary use of exogenous glucocorticoids since they could trigger paraneoplastic Cushing syndrome in these patients. Presentation: Thursday, June 15, 2023

OR11-03 A Novel Mutation In The Ligand-binding Domain Of The NR3C1 Gene Associated With Fluctuating Resistance To Glucocorticoids

Abstract Disclosure: M. Laulhé: None. E. Kuhn: None. J. Bouligand: None. L. Amazit: None. J. Perrot: None. P. Kamenicky: None. M. Lombes: None. J. Fagart: None. S. Viengchareun: None. L. Martinerie: None. Introduction: Constitutive glucocorticoid resistance is associated with mutations in the NR3C1 gene, encoding the Glucocorticoid Receptor (GR). We identified a novel heterozygous point mutation causing fluctuating resistance to glucocorticoid depending on ligand concentrations. Initially, the propositus, a 45-year-old man, was diagnosed with a right adrenal incidentaloma and an ACTH-independent biological hypercortisolism. Shortly after adrenal surgery, plasma cortisol increased again (612 nmol/L) associated with inadequate ACTH levels (122 pg/mL) without any evidence of pituitary adenoma or ectopic ACTH-secreting tumor, suggesting a glucocorticoid resistance syndrome. Methods: We sequenced NR3C1 gene and performed in vitro analysis to assess contribution of this variant to the patient’s phenotype and how it affects biological activity of GR. Results: Exon sequencing of the NR3C1 gene identified a novel missense variant located on exon 5 (NM_000176.3, c.1706 G>A) resulting in substitution of arginine to glutamine at amino acid 569 (GR R569Q) in the Ligand-Binding Domain (LBD) of GR. We characterized transcriptional activity of GR R569Q in HEK 293T cells transiently co-transfected with either GR WT or GR R569Q, together with a luciferase reporter gene construct placed under control of a promoter containing two glucocorticoid responsive elements. We observed a decreased transcriptional activity of GR R569Q (EC50 4.55 nM [3.8;5.3]) compared to GR WT (EC50 0.19 nM [0.15; 0.24]), in response to dexamethasone. Interestingly, GR R569Q exerted a dominant negative effect on GR WT, with a decrease in transcriptional activity of 80% when stimulated with 1 nM dexamethasone (2-way ANOVA test, P<0.0001), which was blunted when stimulated with a 100-fold higher concentration of dexamethasone. As the variant is located within the second nuclear localization signal, we studied nuclear translocation in response to 1 nM cortisol for 1 h. As expected, nuclear-cytoplasmic ratio was lower in patients’ fibroblasts (2.3 ± 0.14 vs 3.0 ± 0.98, ANOVA 2-Way, P < 0.0001) compared with control fibroblasts, as quantified by automated high-throughput microscopy. Three-dimensional modeling revealed that arginine substitution leads to loss of a hydrogen bond stabilizing the LBD structure. This may result in a lower ligand affinity that can be bypassed by high concentrations of agonist. We are currently testing receptor affinity and reversibility of phenotype after hydrogen bond restoration by directed mutagenesis (c.1705 C>A, p.Q569K). Conclusion: Overall, we identified a novel variant of the NR3C1 gene associated with fluctuating GR sensitivity depending on ligand concentration. This finding may provide new insights into mechanisms involved in GR sensitivity. Presentation: Friday, June 16, 2023

A Severe Case of Hypokalemic Metabolic Alkalosis: A Quiz

A Severe Case of Hypokalemic Metabolic Alkalosis: A Quiz

Cushing's syndrome due to atypical carcinoid of the mediastinum

Ectopic Cushing's syndrome, caused by a neuroendocrine tumor (NET), is a rare finding. NETs of the mediastinum are extremely rare. NETs arising from the anterior mediastinum are generally aggressive. They are widely characterized at clinical presentations, and may be asymptomatic or present with atypical symptoms. Prognosis is often poor due to their local recurrence and distant metastasis despite a multimodal approach. A 33-year-old male patient was admitted to our department with a femoral soft tissue abscess, diabetes, and hypokalemia. He had no typical features of Cushing's syndrome. However, with a few simple tests, that is, a basal hormone profile, and low-dose and high-dose dexamethasone suppression tests, we diagnosed this complicated condition of ectopic adrenocorticotrophic hormone (ACTH) secretion. Thoracic computed tomography revealed an anterior mediastinal mass of 35×22 mm. A surgical excision of the tumor was proposed, and intra-operative pathology consultation returned positive for the suspected NET. Immunohistochemically, the tumor cells were positive for CK, CD56, Chromogranin, Synaptophysin, S100, and CD117. No thymic tissue was found. The Ki-67 was 4%. A diagnosis of primary NETs of the mediastinum, intermediate grade (G2), of atypical carcinoids according to WHO 2015 was established. This patient survived with no sequelae, no distant metastasis, no recurrence, and without adjuvant radiotherapy or chemotherapy 2 years after surgery thanks to earlier diagnosis and prompt surgical intervention. Mediastinum ectopic ACTH-secreting tumors are a rare type of cancer. According to recent research, these tumors frequently display more aggressive behavior and are linked to endocrinopathies. It is noted that patient might have a better outcome and a longer survival time due to earlier detection and complete resection of malignancies.

Diagnostic Strategy and Prognostic Factors for Ectopic Adrenocorticotropic Hormone Syndrome: A Retrospective Study of 64 Cases

Introduction: Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a serious life-threatening disease. Tumor localization is crucial in EAS management. This underscores the importance of evaluating imaging methods and prognostic factors to provide a clear basis for patient diagnosis and management. Objective: The aim of this study was to investigate imaging methods and analyze the relevant prognostic factors for EAS. Methods: The retrospective study followed 64 cases of EAS diagnosed between 1992 and 2020. Clinical features, biochemical analysis, and imaging studies were collected, and survival data were followed up and analyzed. Results: Of 64 patients, 41% were female with a mean (±SD) age at diagnosis of 47 ± 16 years. Computed tomography (CT), 18-F fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET)-CT, and octreotide scintigraphy had similar sensitivity in localizing ectopic ACTH-secreting tumors. However, in cases with negative imaging on CT, both of ¹⁸F-FDG PET-CT and octreotide scintigraphy further localized 25% tumors. The combination of all three modalities failed to further increase the sensitivity. Patients with thymic tumors survived longer than those with pulmonary or pancreatic tumors (p = 0.013 and 0.047, respectively). Multivariate analyses showed that hypokalemia (p = 0.004) and treatment modality (p = 0.048) were independent prognostic factors. The optimal serum potassium cutoff based on maximum log-rank statistics (p = 0.012) was 2.90 mmol/L. Conclusion: CT is the first choice for tumor localization in EAS. CT in combination with a nuclear medicine or molecular imaging modality is necessary for further identification of an ectopic source. Serum potassium <2.90 mmol/L is associated with shorter overall survival, and tumor resection plays the most important role in the survival improvement.

Ectopic ACTH syndrome complicated by hypercortisolism-associated urolithiasis. A case report.

We present an elusive case of an ectopic Cushing's syndrome mimicking an autoimmune syndrome induced by adjuvants (ASIA), complicated by rapidly progressive urolithiasis. A 30-year-old female with recent breast augmentation presented for easy bruising, night sweats, nocturia, fatigue, and weight gain. After fulfilling diagnostic criteria for ASIA, she underwent explantation, nonetheless, the patient worsened. Workup revealed an ACTH-dependent Cushing's syndrome with a neuroendocrine tumor in the right lung, confirmed by immunostaining after VAT-FNA. Management was complicated by urolithiasis and COVID-19 infection. She was rendered stone-free and subsequently underwent open lobectomy and mediastinal lymphadenectomy. Pathology confirmed an atypical ACTH-secreting pulmonary carcinoid tumor. She received radiotherapy and was free of recurrence at follow-up. • Nephrolithiasis is a frequent and underestimated complication of Cushing’s syndrome (CS), prevalence soars up to 50 % in adult patients with active CS, and 25% in cured patients in whom certain abnormalities contribute to stone recurrence • Ectopic ACTH secretion (EAS) is a less common cause of Cushing syndrome and is seen in 5 to 10% of cases with endogenous hypercortisolemia. Sudden and dramatic onset of CS often suggests an ectopic ACTH-secreting tumor. • There is no information in any urological clinical practice guideline in relation to management of nephrolithiasis in Cushing’s syndrome, follow-up in glucocorticoid-induced nephrolithiasis should be tailored to each patient.

Use of 18F-FDG PET/CT to Differentiate Ectopic Adrenocorticotropic Hormone-Secreting Lung Tumors From Tumor-Like Pulmonary Infections in Patients With Ectopic Cushing Syndrome.

BackgroundEctopic adrenocorticotropic hormone (ACTH)-secreting lung tumors represent the most common cause of ectopic Cushing syndrome (ECS). Pulmonary opportunistic infections are associated with ECS. The present study aimed to evaluate the usefulness of 18F-FDG PET/CT for differentiating ectopic ACTH-secreting lung tumors from tumor-like pulmonary infections in patients with ECS.MethodsWe retrospectively reviewed the imaging data of 24 patients with ECS who were suspected to have ACTH-secreting lung tumors and underwent 18F-FDG PET/CT between 2008 and 2019. Eleven patients with lung tumors and 4 with pulmonary infections also had additional somatostatin receptor imaging (99mTc-HYNIC-TOC SPECT/CT or 68Ga-DOTATATE PET/CT).ResultsIn total, 18 patients had lung tumors and six had pulmonary infections. The primary source of ECS remained occult in the six patients with pulmonary infections. The maximum standardized uptake value (SUVmax) for pulmonary infections was significantly higher than that for tumors (P = 0.008). Receiver operating characteristic analysis revealed that a cut-off SUVmax of 4.95 helped in differentiating ACTH-secreting lung tumors from infections with 75% sensitivity and 94.4% specificity. For the 11 patients with ACTH-lung tumors, somatostatin receptor imaging (SRI) was positive in 6; while for the 4 with pulmonary infections, SRI was positive in 2. The sensitivity and specificity of somatostatin receptor imaging (SRI) for detecting ACTH-secreting lung tumor was 54.5% and 50%.ConclusionsOur findings suggest that pulmonary infections exhibit significantly higher FDG uptake than ACTH-secreting lung tumors in 18F-FDG PET/CT. An SUVmax cut-off value of 4.95 may be useful for differentiating the two conditions. Our results also suggested that SRI may not be an effective tool for differentiating the two conditions given the relatively low specificity.

Two Distinctive POMC Promoters Modify Gene Expression in Cushing Disease.

ContextMechanisms underlying pituitary corticotroph adenoma adrenocorticotropin (ACTH) production are poorly understood, yet circulating ACTH levels closely correlate with adenoma phenotype and clinical outcomes.ObjectiveWe characterized the 5′ ends of proopiomelanocortin (POMC) gene transcripts, which encode the precursor polypeptide for ACTH, in order to investigate additional regulatory mechanisms of POMC gene transcription and ACTH production.MethodsWe examined 11 normal human pituitary tissues, 32 ACTH-secreting tumors, as well as 6 silent corticotroph adenomas (SCAs) that immunostain for but do not secrete ACTH.ResultsWe identified a novel regulatory region located near the intron 2/exon 3 junction in the human POMC gene, which functions as a second promoter and an enhancer. In vitro experiments demonstrated that CREB binds the second promoter and regulates its transcriptional activity. The second promoter is highly methylated in SCAs, partially demethylated in normal pituitary tissue, and highly demethylated in pituitary and ectopic ACTH-secreting tumors. In contrast, the first promoter is demethylated in all POMC-expressing cells and is highly demethylated only in pituitary ACTH-secreting tumors harboring the ubiquitin-specific protease 8 (USP8) mutation. Demethylation patterns of the second promoter correlate with clinical phenotypes of Cushing disease.ConclusionWe identified a second POMC promoter regulated by methylation status in ACTH-secreting pituitary tumors. Our findings open new avenues for elucidating subcellular regulation of the hypothalamic-pituitary-adrenal axis and suggest the second POMC promoter may be a target for therapeutic intervention to suppress excess ACTH production.

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.

Effects of CRN04894, a Nonpeptide Orally Bioavailable ACTH Antagonist, on Corticosterone in Rodent Models of ACTH Excess

CRN04894 is an orally administered nonpeptide that is a potent and selective antagonist for adrenocorticotropic hormone (ACTH) acting at the melanocortin 2 receptor (MC2R) and is currently under development for the treatment of diseases of ACTH excess such as Cushing’s disease, congenital adrenal hyperplasia, and ectopic ACTH-secreting tumors. Cushing’s disease results from an adenoma derived from pituitary corticotropic cells that secrete excess ACTH, whereas ectopic ACTH syndrome arises from nonpituitary ACTH secreting tumors. Congenital adrenal hyperplasia is a genetic disease that results in cortisol deficiency leading to high levels of ACTH and adrenal androgens. Each of these indications is characterized by high ACTH levels that act on MC2R expressed in the adrenal cortex to drive pathological elevations of adrenally derived steroid hormones. CRN04894 blocks the action of ACTH at MC2R, providing a potential novel treatment for these diseases. Preclinical models of chronic hypercortisolemia include implantation of ACTH-secreting pituitary tumor cells in mice and continuous administration of ACTH via subcutaneously implanted osmotic pumps in rats. These models induce features consistent with human diseases of ACTH excess including hypercortisolemia and hypertrophy of the adrenal glands. We employed both rodent models to examine the pharmacodynamic effects of CRN04894 on corticosterone levels and adrenal gland morphology. In the mouse pituitary tumor model, subcutaneous inoculation of the ACTH-secreting mouse pituitary tumor cell line, AtT-20, into immunodeficient mice resulted in formation of tumors and increased plasma ACTH and corticosterone levels. Repeated daily oral administration of CRN04894 for 14 days dose-dependently and robustly suppressed plasma corticosterone levels in mice with AtT-20 tumors. In the rat model, subcutaneous implantation of osmotic pumps delivering ACTH resulted in increased corticosterone levels, reduction in body weight, and hypertrophy of the adrenal glands after 7 days. Daily oral administration of CRN04894 over 7 days dose-dependently suppressed corticosterone levels, mitigated the effect of ACTH excess on body weight, and rescued the adrenal gland hypertrophy. These findings provide evidence that CRN04894 functions as an effective ACTH antagonist at MC2R to suppress adrenal corticosterone secretion in both mouse and rat models of ACTH excess and hypercortisolemia, thus providing a strong rationale for its potential therapeutic utility in diseases of ACTH excess. This work was supported in part by an SBIR grant from the NIH awarded to Dr. Struthers (R43- DK115245)

A rare case of ectopic ACTH syndrome caused by primary renal neuroendocrine tumor.

SummaryEctopic adrenocorticotropic hormone (ACTH) secretion is responsible for 5–15% of Cushing’s syndrome (CS). Neuroendocrine tumor (NET) is a common cause of ectopic ACTH syndrome (EAS). However, primary renal NET is exceedingly rare. Fewer than 100 cases have been reported and only a few cases presented with CS. Because of its rarity and lack of long-term follow-up data, clinical manifestations, biological behavior and prognosis are not well understood. Here, we report the case of a 51-year-old man who presented with clinical and laboratory findings compatible with EAS. CT scan revealed a lesion of uncertain nature at the lower pole of the left kidney. Octreotide scan found a filling defect at the lower pole of left kidney. It was difficult to determine if this finding was the true etiology or an incidental finding. Unfortunately, the patient’s clinical status rapidly deteriorated with limited medical treatment. The patient underwent left nephrectomy and left adrenalectomy. Histopathological examination confirmed NET with oncocytic features. Immunohistochemistry staining was positive for ACTH. The patient’s condition gradually improved. Additionally, glucocorticoid replacement was required only 6 months during a gradual recovery of hypothalamic pituitary adrenal axis achieved approximately three years after tumor removal. Although extremely rare, primary renal NET should be considered as a cause of EAS particularly in a patient with rapid clinical deterioration. Thorough investigation, early diagnosis and careful management are crucial to reduce morbidity and mortality.Learning pointsPrimary renal NET is an extremely rare cause of ectopic ACTH syndrome.Ectopic ACTH syndrome has a rapid onset with severe clinical manifestations. In this case, the patient’s condition deteriorated rapidly, resulting from severe hypercortisolism. Resection of the tumor is the most effective treatment.Localization of ectopic ACTH-secreting tumors is very challenging. Multimodality imaging including CT, MRI, octreotide scan, and positron emission tomography plays a crucial role in identifying the tumors. However, each imaging modality has limitations.

Functional imaging in ectopic Cushing syndrome.

Ectopic adrenocorticotropic hormone (ACTH)-secreting tumors are commonly small, yet they often lead to fulminant forms of Cushing syndrome. High-resolution functional imaging modalities, such as [Ga]-DOTATATE, have been recently introduced in clinical practice for the identification of neuroendocrine tumors. In this review, we focus on the performance of [Ga]-DOTATATE as a tool for localizing primary and metastatic sources of ectopic Cushing syndrome (ECS). Prompt surgical removal of ectopic ACTH-secreting tumors is the mainstay of therapy in patients with ECS. Detecting such tumors with conventional cross-sectional imaging is often unsuccessful, owing to their small size. [Ga]-DOTATATE has been approved in 2016 by the Federal Drug Administration for imaging well differentiated neuroendocrine tumors. Data regarding the performance of [Ga]-DOTATATE for detecting ectopic ACTH-secreting tumors remain limited, in part owing to the recent introduction of this imaging modality in clinical practice, and in part because of the low prevalence of ECS. Nevertheless, [Ga]-DOTATATE has been reported to be useful in identifying primary and metastatic ectopic ACTH-secreting lesions that were not apparent on other imaging studies, impacting the clinical care of many patients with ECS. [Ga]-DOTATATE-based imaging, which targets the somatostatin receptors abundantly expressed in neuroendocrine tumors, has generally high, although variable resolution in detecting the source(s) of ECS.

MON-167 Use of a Morning Cortisol Level to Predict Recovery of the Hypothalamic-Pituitary-Adrenal (HPA) Axis in Secondary Adrenal Insufficiency Following Remission of Cushing’s Syndrome

BACKGROUND: Remission of Cushing’s syndrome (CS) is generally defined as morning serum cortisol values <5mcg/dL (<138 nmol/L) or Urine Free Cortisol <10-20ug/dL (< 28 – 56 nmol/d) after tumor resection, which reflects suppression of the hypothalamic-pituitary-adrenal (HPA) axis by sustained hypercortisolism. Endocrine Society guidelines recommend glucocorticoid replacement until the HPA axis is normal as assessed by a morning (AM) or post-ACTH stimulation test cortisol level of approximately 18 ug/dL (500 nmol/L) or greater (1). Patients with subnormal cortisol levels remain on glucocorticoid until retested in 3-6 months. The goal of this study was to determine whether a baseline cortisol value predicts a normal response to the ACTH stimulation test. Methods: We reviewed 235 ACTH stimulation (stim) tests conducted on 76 patients with secondary adrenal insufficiency following remission of CS. Patients had resection of a single adrenal gland (n=7), pituitary adenoma [with (n=3) or without (n = 47) subsequent radiation], 70% of pituitary tissue (n=5), or ACTH secreting intrathoracic tumor (n=13). One had an ectopic ACTH secreting tumor in spontaneous remission (n=1). ACTH stim tests were conducted between 0800h and 0900h, 24 hours after the last dose of glucocorticoid, using 250 mcg of cosyntropin intravenously. Cortisol levels were measured just before administration of cosyntropin, and 30 and 60 minutes afterwards. Patients were considered to have passed the test if baseline or peak cortisol values reached > 18mcg/dL. Baseline cortisol values were compared to the ‘pass’ rate. Results: Baseline F values (ug/dL) and passing rates (# pass/total) were:<4: 1/91;4-4.9: 2/27;5-5.9: 8/31;6-6.9: 2/21;7-7.9: 7/25;8-8.9: 4/12;9-9.9: 8/12;>10 - < 15: 6/1115 – 19.5: 5/5Thus, Am cortisol values >9 ug/dl were significantly more likely to predict a normal response to ACTH stim than lower values (p<0.0001). ACTH values (n=184) did not predict peak F levels. However, no patient with ACTH value <5 pg/ml passed the test; all had peak F values of 0-10.5. Conclusion: Baseline cortisol can be a guide as to whether the more costly stimulation test is needed. In the small cohort with baseline 0800h – 0900h cortisol >15 ug/dL, all passed the test, suggesting that it is not needed in such patients. We recommend use of an ACTH stimulation test to assess recovery of the HPA axis when a morning cortisol reaches 9 mcg/dL, with an expected pass rate of about 66%. Reference: 1. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO et al. Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 100:2807, 2015.

MON-250 Late Diagnosis of ACTH-secreting Pulmonary Neuroendocrine Tumor by Repeated 68Ga Dotatate Pet/ct: Influence of Tumor Size in Abnormal Uptake?

Background: 68Ga DOTATATE PET/CT (68Ga-PET) has been proposed as a superior method in identifying ectopic ACTH syndrome (EAS). However, recent systematic review suggests its sensitivity is not as high as believed (1). We report a challenging case of EAS whose source was uncovered only after repeated 68Ga-PET. Clinical Case: A 15‐year-old male presented with rapid onset of typical features of Cushing’s syndrome (CS) and metabolic impairment. Hormone evaluation confirmed severe ACTH-dependent CS. Pituitary transsphenoidal surgery was performed due to positive responses in desmopressin stimulation and high dose dexamethasone suppression test, in addition to a 4 mm nodule in pituitary MRI. No tumor was found in surgical specimen and no hormonal improvement was observed after surgery. Inferior petrosal sinus sampling demonstrated no central to peripheral ACTH gradient. Neck US, thorax/abdomen/pelvis CT were negative and PET-CT/FDG was inconclusive. OctreoScan® identified anomalous uptake on left mediastinum and led the patient to a thoracic surgery (TS) with nodule resection at left hilum. Pathology confirmed ACTH positive 10 mm neuroendocrine tumor (NET) infiltrating a lymph node. The patient had transient clinical and hormonal improvement, with recurrence 7 months later. Thoracic CT (T-CT) showed a 7 mm nodule on inferior segment of superior left lobe, PET-CT/FDG and OctreoScan® were negative but abnormal uptake was verified by 68Ga-PET in subcarinal area. A sub centimetric lymph node was resected and pathology confirmed ACTH positive NET, although the patient did not achieve remission. Octreotide LAR, cabergoline and ketoconazole did not control hypercortisolism and bilateral adrenalectomy was performed. Then, T-CT showed stable lung nodule and 2nd 68Ga-PET was negative. One year later, T-CT evidenced growth of lung nodule to 15 mm and 3rd 68Ga-PET demonstrated for the first time, abnormal uptake in this area. The patient underwent resection of left superior lung lobe along with ipsilateral hilar lymph nodes, and histopathology study revealed an ACTH-secreting atypical pulmonary carcinoid tumor with Ki67 of 10% and 5 out of 11 lymph nodes affected. ACTH fell from 288 to 64 pg/mL after surgery. Conclusion: Despite the high sensitivity attributed to 68Ga-PET, false negatives have been reported. In the present case, primary tumor was evidenced by 68Ga-PET seven years after the first resection of a metastatic lymph node, in the 3rd 68Ga-PET assessment and after tumor growth. This adds to the evidence that further studies are needed to better assess the accuracy of 68Ga-PET for EAS. Reference: [1] Varlamov et al. Diagnostic utility of Gallium‐68‐somatostatin receptor PET/CT in ectopic ACTH‐secreting tumors: a systematic literature review and single‐center clinical experience. Pituitary 2019; 22:445–455

SUN-904 Ga68 Dotatate Detects Ectopic ACTH Secreting Atypical Carcinoid Tumor

Title Ga68 DOTATATE detects Ectopic ACTH secreting Atypical Carcinoid tumor Introduction Ga-68 DOTATATE PET/CT has been shown to have a significant impact in localizing Ectopic ACTH secreting tumors especially those that are not identified on conventional imaging (CT, MRI). We present a person with a tumor that was reported benign (on biopsy) elsewhere but was found to be the source of the Cushings syndrome and was localized on Ga-68 DOTATATE PET/CT, pathology confirming atypical carcinoid tumor after surgical excision. Discussion She was a 63-year-old who presented with a severe proximal myopathy, high urinary free cortisol- 911.6 (µg/day) (<45), elevated ACTH 104(<63), and negative Inferior Petrosal Sinus Sampling. The CT scan demonstrated a small nodule at the right lung base. Axial Ga-68 DOTATATE PET images demonstrated radiotracer activity in the lesion, SUV max of 7.15. Fused Coronal Images showed a 1.9 cm radiotracer avid nodule, that was detected in the medial segment of the right middle lobe. The patient underwent a pulmonary wedge resection. H and E stain of the tumor -Immunohistochemical stains demonstrated that the tumor was strongly positive for synaptophysin and INSM-1 (markers of neuroendocrine differentiation) and the mitotic count was up to 2–3 mitoses per 10 high-power fields, supporting diagnosis as an atypical carcinoid tumor. The patient had significant improvement of symptoms post excision. Somatostatin Receptor (SSR) based tracer Ga-68 DOTATATE PET/CT has a reported sensitivity for detection of 50 % in occult neuroendocrine tumors (NET), with an overall sensitivity of 64 % in a systematic review. It has been shown in retrospective reviews to help with clinical management both at initial diagnosis as well as follow up of Ectopic Cushings in approximately 65% of the cases. SSR analogue tracers like DOTATATE have been noted to be slightly better than FDG PET/CT at localizing ACTH producing bronchial carcinoids while small-cell lung cancers and other aggressive tumors are better visualized on FDG PET. The favorable aspect of Ga-68 DOTATATE includes great tumor to background ratio and the half-life of Gallium 68 that is suitable for transport and delivery. Metastatic NET in conjunction with ectopic Cushing syndrome can be also be treated with peptide receptor radionuclide therapy using either 90Y-DOTATOC and 177Lu-DOTATATE (both SSR based) resulting in improved clinical outcomes.

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.

Diagnostic utility of Gallium-68-somatostatin receptor PET/CT in ectopic ACTH-secreting tumors: a systematic literature review and single-center clinical experience.

Tumors causing ectopic Cushing's syndrome (ECS) are often not visible with conventional imaging. Gallium-68-DOTATATE, DOTATOC, and DOTANOC positron emission tomography/computed tomography (68Ga-SSTR PET/CT) reportedly exhibits greater sensitivity in identifying an ECS source, however, evidence is limited to mainly case reports and a few small retrospective studies. Previous systematic ECS imaging review has shown 68Ga-SSTR PET/CT sensitivity is similar to CT (81.8%) in histologically-proven cases and is 100% in covert-cases, however, the number of patients was small and no occult cases were reported. We performed a systematic literature review of 68Ga-SSTR PET/CT use in ECS patients. We also report 6 consecutive patients with confirmed active and occult ECS who underwent 68Ga-DOTATATE PET/CT and were followed at our institution between 2014 and 2019. We identified 33 articles (23 case-reports, 4 case-series, 5 retrospective studies and 1 prospective study) detailing 68Ga-SSTR PET/CT in 69 ECS patients. Overall 68Ga-SSTR PET/CT sensitivity was 64.0%, while in histologically confirmed cases (67 lesions), sensitivity was 76.1%. There were two false-positives cases, both in the adrenal glands. In covert cases, 68Ga-SSTR PET/CT identified 50% of lesions. There were ten occult cases where all imaging failed to identify an adrenocorticotropic hormone source; source remains unknown. In our case series, 68Ga-DOTATATE PET/CT showed decreased uptake in pancreatic neuroendocrine tumor in one patient and did not help identify an ECS source in 5 patients. Both this systematic literature review, the largest to date, and our single- center experience demonstrate a lower than previously reported 68Ga-SSTR PET/CT sensitivity for ECS, especially in occult lesions. We suggest that the data on 68Ga-SSTR PET/CT in ECS is subject to publication bias, and false-negatives are likely underreported; it's diagnostic value for ECS needs further study.

The Clinical Impact of [68 Ga]-DOTATATE PET/CT for the Diagnosis and Management of Ectopic Adrenocorticotropic Hormone - Secreting Tumours.

Localization of ectopic ACTH-secreting tumours causing Cushing syndrome (ECS) is essential for clinical management, yet often difficult. [68 Ga]-DOTATATE PET/CT ([68 Ga]-DOTA-(Tyr3 )-octreotate)] is an FDA-approved high-resolution diagnostic tool for imaging neuroendocrine tumours. Data on the clinical utility of [68 Ga]-DOTATATE in patients with ECS, however, are scarce. The objectives of this study were to determine the efficacy for ECS localization and the clinical benefit of [68 Ga]-DOTATATE imaging. We conducted a retrospective review of all cases with ECS evaluated with [68 Ga]-DOTATATE from November 2016 through October 2018 at three referral centres. The clinical benefit of [68 Ga]-DOTATATE was based on detection of new tumours and resultant changes in management. Over the study period, 28 patients with ECS underwent [68 Ga]-DOTATATE: 17 for identification of the primary tumour and 11 during follow-up. [68 Ga]-DOTATATE identified the suspected primary ECS in 11/17 patients (65%). Of these, nine patients underwent surgery: eight with confirmed ECS (5 bronchial, 1 thymic, 1 pancreatic and 1 metastatic neuroendocrine tumour of unknown primary origin) and one patient with a false-positive scan (adrenal gland). Of the 11 patients with ECS who underwent [68 Ga]-DOTATATE evaluation during follow-up, the study led to changes in clinical management in 7/11 (64%) patients. [68 Ga]-DOTATATE is sensitive in detecting primary and metastatic ECS, often identifies occult tumours after conventional imaging, and impacts clinical care in the majority of patients.

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

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