Clinical profile and treatment outcomes of patients with ectopic ACTH syndrome compared to Cushing disease: a single-center experience.

PURPOSE: We aimed to evaluate and compare the clinical, biochemical and radiological profile and outcomes of patients with ectopic ACTH syndrome (EAS) and Cushing disease (CD) treated over a period of 10 years (2013-2022). METHODS: In this ambispective observational study, we collected data for 146 patients with ACTH-dependent CS (EAS, n = 23; CD, n = 94; occult ACTH source, n = 29). Relevant details were filled in a predesigned proforma and outcomes were ascertained at the most recent visit. RESULTS: EAS was more common in males (65.2 vs. 27.6%, p < 0.001). Patients with EAS had a shorter duration of symptoms [12 (6-12) vs. 31.5 (15-48) months, p < 0.001] and were more likely to have hypokalemia (82.6 vs. 21.0%, p = 0.001), pedal edema (65.2 vs. 34.2%, p = 0.015), weight loss (34.8 vs. 4.0%, p < 0.001) and systemic infection (30.4 vs. 6.5%, p = 0.006). They also had significantly higher 8 a.m. serum cortisol, midnight serum and salivary cortisol and 8 a.m. plasma ACTH levels. Bronchial carcinoid (n = 10, 43.5%) was the most common etiology of EAS. Bilateral adrenalectomy was performed in 11 (47.8%) patients with EAS. Eight patients (34.8%) with EAS died at the last follow-up, of whom 7 (87.5%) had metastatic disease. In CD group, overall remission rate was 69.4% (56.1%, early and 13.3%, delayed) and 26.3% of patients with an initial remission had recurrence. CONCLUSIONS: Bronchial carcinoid was the most common cause of EAS in our cohort. Bilateral adrenalectomy was performed in approximately every 1 in 2 patients with EAS and approximately every 1 in 3 patients expired till the last follow-up.

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.

MANAGEMENT OF ENDOCRINE DISEASE: Cushing's syndrome due to ectopic ACTH secretion: an expert operational opinion.

Ectopic ACTH syndrome (EAS) is rare but is frequently a severe condition because of the intensity of the hypercortisolism that may be dissociated from the tumoral condition. EAS should often be considered as an endocrine emergency requiring an emergency response both in terms of diagnostic procedures and therapeutic interventions. Patient management is complex and necessitates dual skills, in the diagnosis and treatment of CS and in the specific management of neuroendocrine tumors (NET). Therefore, initial management should be performed ideally by experienced endocrinology teams in collaboration with specialized hormonal laboratory, modern imaging platforms and intensive care units. Diagnostic procedures vary according to the endocrine and tumoral contexts but should be reduced to a minimum in intense hypercortisolism. Preventive and curative treatments of cortisol-induced comorbidities, non-specific management of hypercortisolism and etiological treatments should be considered simultaneously. Therapeutic strategies vary according to (1.) the intensity of hypercortisolism, the general condition of the patient and associated comorbidities and (2.) the tumoral status, ranging from resectable ACTH secreting tumors to non-resectable metastatic endocrine tumors or occult tumors. The ideal treatment is complete excision of the ACTH-secreting tumor that can be performed rapidly or after preoperative preparation using cortisol-lowering drugs. When this is not possible, the therapeutic strategy should be discussed by a multidisciplinary experienced team in a personalized perspective and include variable combinations of pharmacological agents, bilateral adrenalectomy and non-specific tumoral interventions. Here we discuss the diagnosis and therapeutic strategies including the modern, currently available tools and emphasize on the operational effectiveness of care.

Ectopic ACTH Syndrome in a Child With Abdominal Ewing Sarcoma: A Rare Paraneoplastic Phenomenon.

Ectopic adrenocorticotropic hormone syndrome is a paraneoplastic phenomenon rarely seen in pediatrics and rarely described in Ewing sarcoma. We report a 15-year-old boy with abdominal Ewing sarcoma and clinical and laboratory findings of ectopic adrenocorticotropic hormone syndrome that promptly resolved with treatment of the tumor.

An unusual manifestation of olfactory neuroblastoma.

A 62-year-old woman presented with an 11-month history of worsening nasal symptoms of rhinorrhoea, anosmia, nasal congestion and intermittent epistaxis. MRI revealed a large mass in the upper nasal vault. Biopsy of the mass revealed an olfactory neuroblastoma. While waiting resection, she acutely developed severe proximal muscle weakness, lethargy and lower extremity oedema. Blood glucose was elevated, and hypokalaemic metabolic alkalosis was noted. Elevated serum cortisol level of 95.7 µg/dL (8.7-22.4 µg/dL) and markedly elevated 24-hour urinary cortisol level of 6962.3 µg/24 hours (4.0-50.0 µg/24 hours) with concurrent adrenocorticotropic hormone (ACTH) level of 171 pg/mL (6-58 pg/mL) were suggestive of an ACTH-dependent source of hypercortisolism. A subsequent positive high-dose dexamethasone suppression test was consistent with ectopic ACTH production. She underwent near-total resection of the right nasal mass followed by radiotherapy, resulting in complete resolution of signs and symptoms of cortisol excess.

Ectopic ACTH syndrome complicated by multiple opportunistic infections treated with percutaneous ablation of the adrenal glands.

Ectopic adrenocorticotropic hormone (ACTH)-related Cushing's syndrome can lead to multiple complications including severe immunosuppression. If the ACTH-secreting tumour cannot be found, definitive treatment is surgical adrenalectomy, typically followed by glucocorticoid replacement. Here, we present a case of fulminant respiratory failure secondary to coinfection with Pneumocystis jirovecii and cytomegalovirus in a patient with ectopic ACTH-dependent Cushing's syndrome with occult primary. Due to significant deconditioning, she was unable to undergo definitive adrenalectomy and instead underwent percutaneous microwave ablation of the adrenal glands.

Cushing's syndrome in infancy due to ectopic ACTH secretion by a sacro-coccygeal teratoma.

BACKGROUND: Adenocorticotropic hormone (ACTH)-dependent Cushing's syndrome in infancy is extremely rare. We describe the case of a sacro-coccygeal ectopic ACTH-secreting immature teratoma in an infant who also presented the triad of defects characteristic of Currarino syndrome. CASE PRESENTATION: A girl was born with a large immature teratoma in the sacro-coccygeal region associated with anal atresia. At the age of 7 days, the concentration of α-fetoprotein (AFP) was above the age-specific normal range. Two non-radical surgical excisions of the tumour were performed. At the age of 7 months, she developed polyphagia, acne, hirsutism, hypertension and hypokalemia with elevated ACTH and absence of serum cortisol circadian rhythm. Immunostaining of tumour tissue showed ACTH-immunoreactive cells. Due to unsuccessful therapy with ketoconazole and resistance to antihypertensive medications [blood pressure (BP) 210/160 mmHg], metyrapone was administered, which controlled her ACTH and cortisol levels in the normal range. Following further removal of tumour bulk after three operations during the first year of life, there was a decrease of BP to normal values. CONCLUSIONS: A rare case of ectopic ACTH syndrome causing Cushing's syndrome in infancy in the context of Currarino syndrome is reported. Radical surgery has resulted in excision of the tumour and current control of Cushing's syndrome.

Ectopic Cushing's syndrome in light of modern diagnostic techniques and treatment options.

Ectopic adrenocorticotropic hormone secretion (EAS) is responsible for approximately 10-15% cases of Cushing's syndrome. EAS is associated with various tumors such as small cell lung cancer and well-differentiated bronchial or gastrointestinal neuroendocrine tumors. Hormonal diagnostics include assessments in basic conditions as well as dynamic tests, such as the high-dose dexamethasone suppression test and corticotrophin releasing hormone (CRH) stimulation test. Treatment selection depends on the type of tumor and its extent. In the case of neuroendocrine tumors, the main treatments are surgery and administration of somatostatin analogs that may be additionally radiolabeled for targeted radiotherapy. The tumor histology and the presence and control of hypercortisolemia and metastases are of major importance in prognosis. In this article we presented the principles of modern hormonal and imaging diagnostics techniques as well as the key issues associated with treatment of ACTH-dependent Cushing's syndrome due to EAS.

[Paraneoplastic Cushing's syndrome, a real diagnostic and therapeutic challenge: A case report and literature review]. / Le syndrome de Cushing paranéoplasique, un vrai défi diagnostique et thérapeutique: à propos d'un cas et revue de la littérature.

INTRODUCTION: Paraneoplastic 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 (18)FDG-PET scan and (18)DOPA-PET scan. CASE REPORT: We 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, (18)FDG-PET scan found a non-specific mild hypermetabolism of the lung nodule, and the (18)DOPA-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. CONCLUSION: This case illustrates the dilemma between the need for morphological diagnosis of the ectopic ACTH source and control of the life-threatening hypercortisolism. (18)FDG-PET scan and (18)DOPA-PET scan should be considered early as a secondary diagnostic tool when conventional imagery fails to show any tumor.

ACTH-secreting pancreatic neoplasms associated with Cushing syndrome: clinicopathologic study of 11 cases and review of the literature.

Adrenocorticotropic hormone (ACTH)-secreting pancreatic neuroendocrine tumors (PanNETs), although rare, are responsible for about 15% of ectopic Cushing syndrome (CS). They represent a challenging entity because their preoperatory diagnosis is frequently difficult, and clear-cut morphologic criteria useful to differentiate them from other types of PanNETs have not been defined. Ectopic ACTH secretion associated with CS can also be rarely due to pancreatic acinar cell carcinoma (ACC) and pancreatoblastoma, rare tumor types with morphologic features sometimes overlapping those of PanNETs and, for this reason, representing a diagnostic challenge for pathologists. We herein describe the clinicopathologic and immunohistochemical features of 10 PanNETs and 1 ACC secreting ACTH and associated with CS together with an extensive review of the literature to give the reader a comprehensive overview on ACTH-producing pancreatic neoplasms. ACTH-secreting PanNETs are aggressive neoplasms with an immunohistochemical profile that partially overlaps that of pituitary corticotroph adenomas. They are generally large and well-differentiated neoplasms without distinctive histologic features but with signs of aggressiveness including vascular and perineural invasion. They are more frequent in female individuals with a mean age of 42 years. At 5 and 10 years after diagnosis, 35% and 16.2% of patients, respectively, were alive. ACTH-secreting ACCs and pancreatoblastomas are very aggressive pediatric tumors with a poor prognosis. Using an appropriate immunohistochemical panel including ACTH, ß-endorphin, trypsin, and BCL10 it is possible to recognize ACTH-secreting PanNETs and to distinguish them from the very aggressive ACTH-secreting ACCs.

Ectopic ACTH-secreting syndrome: a single-center experience.

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

Hypercortisolaemia due to ectopic adrenocorticotropic hormone secretion by a nasal paraganglioma: a case report and review of the literature.

BACKGROUND: Adrenocorticotropic hormone-producing extraadrenal paragangliomas are extremely rare. We present a case of severe hypercortisolemia due to ectopic adrenocorticotropic hormone secretion by a nasal paraganglioma. CASE PRESENTATION: A 70-year-old Caucasian woman, was emergently admitted to our department with supraventricular tachycardia, oedema of face and extremities and hypertensive crisis. Initial laboratory evaluation revealed severe hypokalemia and hyperglycemia without ketoacidosis, although no diabetes mellitus was previously known. Computed tomography revealed a large tumor obliterating the left paranasal sinus and a left-sided adrenal mass. After cardiovascular stabilisation, a thorough hormonal assessment was performed revealing marked adrenocorticotropic hormone-dependent hypercortisolism. Due to the presence of a cardiac pacemaker magnetic resonance imaging of the hypophysis was not possible. [68Ga-DOTA]-TATE-Positron-Emission-Tomography was performed, showing somatostatin-receptor expression of the paranasal lesion but not of the adrenal lesion or the hypophysis. The paranasal tumor was resected and found to be an adrenocorticotropic hormone-producing paraganglioma of low-proliferative rate. Postoperatively the patient became normokaliaemic, normoglycemic and normotensive without further need for medication. Genetic testing showed no mutation of the succinatdehydrogenase subunit B- and D genes, thus excluding hereditary paragangliosis. CONCLUSION: Detection of the adrenocorticotropic hormone source in Cushing's syndrome can prove extremely challenging, especially when commonly used imaging modalities are unavailable or inconclusive. The present case was further complicated by the simultaneous detection of two tumorous lesions of initially unclear biochemical behaviour. In such cases, novel diagnostic tools - such as somatostatin-receptor imaging - can prove useful in localising hormonally active neuroendocrine tissue. The clinical aspects of the case are discussed and relevant literature is reviewed.

The search for ectopic ACTH production in a 9-year-old boy.

Ectopic ACTH syndrome (EAS) is rare in children and is challenging to differentiate from Cushing's disease. A 9-year-old boy presented with a history of worsening fatigue, muscle weakness, weight gain and acne, and he appeared cushingoid with central obesity and hyperpigmentation of his palmar creases. Investigations demonstrated an elevated ACTH and an elevated morning cortisol that did not suppress with low or high dose dexamethasone suppression tests. Brain imaging inconsistently showed a small pituitary lesion. Chest and abdomen computed tomography (CT) showed adrenal hyperplasia and a liver hemangioma. [18F]fluorodeoxyglucose positron emission tomography CT was normal. Ultrasound and abdominal magnetic resonance imaging (MRI) also showed a liver hemangioma. Bilateral inferior petrosal sinus sampling, however, was consistent with ectopic ACTH production. An octreotide scan revealed a small focus of increased activity in the liver, which was the likely source of ectopic ACTH production. The patient was managed with metyrapone followed by a wedge liver resection. Pathology showed a well-differentiated neuroendocrine tumor (NET) that stained positive for ACTH. Post-operatively, the signs and symptoms of EAS are resolving and his hypothalamic-pituitary-adrenal axis is recovering. This case describes the first pediatric patient with EAS caused by a liver NET. It illustrates the challenges in localizing the source of ectopic ACTH and treating this rare condition.

Clinical features and management of ectopic ACTH syndrome at a single institute in Japan.

Ectopic ACTH syndrome (EAS) is a diagnostic challenge because it is often indistinguishable from Cushing's disease. We describe our series of EAS patients referred to us during 1992-2009. Among 16 cases (9 females / 7 males), with mean age of 58.4 ± 19.0yr, the ectopic source was identified in ten (proven EAS), whereas unidentified in six (occult/unknown EAS). Their salient clinical manifestations included Cushingoid feature (88%), skin pigmentation (88%), profound hypokalemia (88%), hypertension (75%), diabetes/impaired glucose tolerance (75%), hyperlipidemia (69%), and severe infection (44%). Dynamic endocrine tests revealed markedly elevated plasma ACTH levels (211 ± 116pg/mL) and cortisol levels (60.9 ± 30.1µg/dL) which showed resistance to overnight high-dose (8mg) dexamethasone suppression test in 15 (94%) and unresponsiveness to CRH stimulation in 12 (75%). No ACTH gradient during inferior petrosal sampling was noted in 13 of 15 (87%). Imaging tests by CT/MRI identified the tumors in 8 of 16 (50%), in 4 of 11 (36%) and 4 of 6 (66.7%) octreotide-responders by somatostatin receptor scintigraphy, but in only one of 9 (11.1%) by FDG-PET scan. Six cases deceased, including small cell carcinoma (2) and adenocarcinoma (1) of lung, neuroendocrine carcinoma of pancreas (1) and stomach (1), and olfactory neuroblastoma (1), whereas 4 cases survived after removal of the tumors, including bronchial carcinoid tumor (3) and thymic hyperplasia (1). Six occult/unknown EAS patients survived for 67.5 months after medical treatment with metyrapone to control hypercortisolism. Thus, various endocrine tests combined with imaging studies are required to correctly localize the tumors. Control of hypercortisolemia by metyrapone, even if tumor is unrecognized, is critical for better prognosis, and the long-term follow-up by repeated endocrine and imaging tests is mandatory.

First report of ectopic ACTH syndrome and PTHrP-induced hypercalcemia due to a hepatoblastoma in a child.

CONTEXT: Only occasionally, endocrine-active tumors develop directly from hepatic tissue, and may lead to paraneoplastic syndromes (PNS). PNS mostly accompany malignancy of adulthood and are exceedingly rare in children. PATIENT: A girl aged 6 years and 9 months presented with a 2-month history of rapidly progressive weight gain, abdominal distension, and polyuria/pollakiuria accompanied by short episodes of abdominal pain. She showed the typical clinical features of Cushing's syndrome and a huge hepatic mass. An abdominal computed tomography (CT) scan revealed a large liver tumor. Blood glucose and serum calcium were greatly elevated. DESIGN AND OBJECTIVE: Case report describing the causative relationship of the clinical findings. METHODS: Physical examination; ultrasound of the abdomen; CT scan of the abdomen and the chest; conventional X-rays; routine hematology; blood chemistry and multiple parameters of calcium and phosphorus metabolism; multisteroid analysis in serum and urine; adrenocortical stimulation and suppression tests; histopathological assessment of the resected tumor; immunohistochemistry for ACTH, beta-endorphin, corticotrophin-releasing hormone (CRH), and PTH-related peptide (PTHrP); electron microscopy of tumor cells; ACTH and CRH extraction from the tumor tissue; and clinical follow-up for more than 20 years. RESULTS: Giant hepatoblastoma (HB; approximately 1000 ml volume) of the right lobe of the liver with combined ectopic ACTH syndrome and PTHrP-induced tumor-associated hypercalcemia. Wide local excision and polychemotherapy led to complete reversal of the paraneoplastic phenotype. CONCLUSIONS: This is the first report of an endocrine-active HB causing both Cushing's syndrome and PTHrP-related 'humoral hypercalcemia of malignancy'. This information should be added to the well-known beta-human chorionic gonadotropin-related paraneoplastic effects of HB in children.