Ectopic Cushing's Syndrome Research Articles

Ectopic Cushing's syndrome

Ectopic Cushing's syndrome

Limited Invasive Protocol: Optimizing Diagnostic Modalities in Corticotropin Mediated Cushing Syndrome

BackgroundTo limit the role of bilateral inferior petrosal sinus sampling (BIPSS) in distinguishing between Cushing disease (CD) and ectopic Cushing syndrome (ECS), recent reports have proposed a noninvasive approach based on a combination of biochemical testing and radiological imaging as an alternative to the conventional invasive strategy (CIS). However, this strategy requires further validation. The current study aimed to evaluate 2 limited invasive protocols (LIP-1 and LIP-2) in limiting the role of BIPSS while maintaining a diagnostic accuracy similar to that of CIS. MethodsThis was a single-center study conducted on individuals with corticotropin-dependent Cushing syndrome. The LIPs were based on performing high-dose dexamethasone suppression (>50% cut-off in first [LIP-1] and >80% in second [LIP-2]) and magnetic resonance imaging of the sella in all individuals and selective use of computed tomography of the chest and abdomen before BIPSS. These LIPs were evaluated for limiting the use of BIPSS, their accuracy, and cost in comparison to CIS. ResultsOf the 206 individuals, 114 (97 of CD and 21 of ECS) were eligible for the current study. Using LIP-1, LIP-2, and CIS, BIPSS could have been avoided in 62.3%, 35.9%, and 25.4% of individuals, respectively. The positive predictive value for CD using LIP-1 and LIP-2 was 98.9% and 100%, respectively. The cost per patient evaluated using LIP-1, LIP-2, and CIS was $602.21, $966.81, and $1107.78, respectively. ConclusionLIPs represent an equally accurate, less invasive, and more cost-effective alternative to the CIS for distinguishing between CD and ECS.

Management of adrenocorticotropic hormone-secreting neuroendocrine tumors and the role of bilateral adrenalectomy in ectopic Cushing syndrome

BackgroundNeuroendocrine tumors can cause ectopic Cushing syndrome, and most patients have metastatic disease at diagnosis. We identified risk factors for outcome, evaluated ectopic Cushing syndrome management, and explored the role of bilateral adrenalectomy in this population. MethodsThis was a retrospective study including patients with diagnosis of ectopic Cushing Syndrome secondary to neuroendocrine tumors with adrenocorticotropic hormone secretion treated at our quaternary referral center over a 40-year period (1980–2020). ResultsSeventy-six patients were included. Mean age at diagnosis was 46.3 ± 15.8 years. Most patients (N = 61, 80%) had metastases at ectopic Cushing syndrome diagnosis. Average follow-up was 2.9 ± 3.7 years (range, 4 months–17.2 years). Patients with neuroendocrine tumors before ectopic Cushing syndrome had more frequent metastatic disease and resistant ectopic Cushing syndrome. Patients with de novo hyperglycemia, poor neuroendocrine tumor differentiation, and metastatic disease had worse survival. Of those with nonmetastatic disease, 8 (53%) had ectopic Cushing syndrome resolution after neuroendocrine tumor resection, 3 (20%) were medically controlled, and 4 (27%) underwent bilateral adrenalectomy. In patients with metastatic neuroendocrine tumors, hypercortisolism was initially medically managed in 92%, 3% underwent immediate bilateral adrenalectomy, 2% had control after primary neuroendocrine tumor debulking, and 2% were lost to follow-up. Medical treatment resulted in hormonal control in 7 (13%) patients. Of the 49 patients with metastatic disease and medically resistant ectopic Cushing syndrome, 23 ultimately had bilateral adrenalectomy with ectopic Cushing syndrome cure in all. ConclusionPatients with neuroendocrine tumors before ectopic Cushing syndrome development were more likely metastatic and had worse survival. De novo hyperglycemia and poor neuroendocrine tumor differentiation were predictive of worse prognosis. Medical control of hypercortisolism is difficult to achieve in patients with neuroendocrine tumors–ectopic Cushing syndrome. Well-selected patients may benefit from bilateral adrenalectomy early in the treatment algorithm, and multidisciplinary management is essential in this complex disease.

Ectopic Cushing's syndrome from an ACTH-producing pheochromocytoma with a non-functioning pituitary adenoma.

SummaryAn adrenocorticotropic hormone (ACTH)-producing pheochromocytoma (PCC)/paraganglioma is the cause of ectopic Cushing’s syndrome (CS) in 5.2% of cases reported in the literature. We present a previously healthy 43-year-old woman admitted to our hospital with cushingoid features and hypertensive urgency (blood pressure = 200/120 mmHg). Her 24-h urinary free cortisol was >4270 nmol/day (reference range (RR) = 100–380 nmol/day) with a plasma ACTH of 91.5 pmol/L (RR: 2.0–11.5 pmol/L). Twenty-four-hour urinary metanephrines were increased by 30-fold. Whole-body CT demonstrated a 3.7-cm left adrenal mass with a normal-appearing right adrenal gland. Sellar MRI showed a 5-mm sellar lesion. MIBG scan revealed intense uptake only in the left adrenal mass. She was managed pre-operatively with ketoconazole and phenoxybenzamine and underwent an uneventful left laparoscopic adrenalectomy, which resulted in biochemical resolution of her hypercortisolemia and catecholamine excess. Histology demonstrated a PCC (Grading System for Adrenal Pheochromocytoma and Paraganglioma score 5) with positive ACTH staining by immunohistochemistry. A PCC gene panel showed no mutations and there has been no evidence of recurrence at 24 months. This case highlights the difficult nature of localizing the source of CS in the setting of a co-existing PCC and sellar mass.Learning pointsAn adrenocorticotropic hormone (ACTH)-producing pheochromocytoma (PCC) is an important item to be considered in all patients presenting with ectopic Cushing’s syndrome (CS).In exceptionally rare cases, patients with ectopic CS may present with multiple lesions, and a systematic approach considering all potential sources is crucial to avoid misdiagnosis.CS with a large adrenal mass but lacking contralateral adrenal atrophy should raise suspicion of an ACTH-dependent process.In patients with clinical suspicion of PCC, clinicians should be mindful of the use of steroids and beta-blockers without appropriate alpha blockade as they may precipitate an adrenergic crisis.

Diurnal Salivary Cortisol Profiles in Patients with Cushing's Syndrome.

Quantification of salivary cortisol is one of the highly sensitive and specific screening parameters for Cushing's syndrome (CS). However, only late-night salivary cortisol is part of the standard screening procedure. In this study, we aimed to analyze salivary cortisol day profiles in patients with different types of CS to test whether specific patterns might be relevant for diagnosis and subtyping. Among 428 patients including those with confirmed Cushing's syndrome (N=111, of those 75 with Cushing's disease, 27 patients with adrenal CS and nine patients with ectopic CS), autonomous cortisol secretion (N=39) or exclusion of CS (control group, N=278) salivary cortisol was measured five times a day. At each of the five time points, salivary cortisol was significantly higher in patients with CS compared to the control group (p≤0.001). Using the entire profile instead of one single salivary cortisol at 11 p.m. improved diagnostic accuracy (85 vs. 91%) slightly. Patients with ACTH-dependent CS had higher salivary cortisol levels than patients with adrenal CS. Also, morning cortisol was significantly higher in patients with ectopic CS than in patients with Cushing's disease (p=0.04). Nevertheless, there was a strong overlap between diurnal profiles, and the diagnostic yield for subtyping was low. The study results show that using diurnal salivary cortisol profiles for CS diagnosis results in a limited increase in diagnostic accuracy. With significant differences between Cushing subtypes, cortisol profiles are not useful in everyday clinical practice for subtyping of CS.

Demystifying the Relevance of Size Amongst Macro- and Micro-Corticotropinoma: Experience in 206 Patients.

Objective:In individuals with adrenocorticotrophic hormone (ACTH)-dependent Cushing’s syndrome (CS), to estimate the differences between micro-corticotropinoma (size ≤6 mm and 6-10 mm), macro-corticotropinoma (>10 mm) and ectopic Cushing’s syndrome (ECS), in relation to their epidemiological, clinical and biochemical parameters.Methods:In individuals with CS, the clinical and hormonal parameters, and magnetic resonance imaging of sella were collected from 1984 to 2019. A total of 138 cases of micro-corticotropinoma, 47 cases of macro-corticotropinoma and 21 cases of ECS were compared.Results:Except for size, there were no differences in biochemical and hormonal parameters of macro- and micro-corticotropinoma, irrespective of their size (≤6 mm, 6-10 mm and >10 mm). In comparison to Cushing’s disease (CD), individuals with ECS had a male predominance (F:M ratio of 2.4:1 vs. 0.5:1), shorter duration from onset of symptoms to diagnosis (24 vs. 12 months). They also had a higher ACTH (139 vs. 65.8 pg/ml), 0800h cortisol (1200 vs. 880 nmol/l), 2300h cortisol (1100 vs. 700 nmol/l) and cortisol levels after high dose dexamethasone suppression test (1050 vs. 244.5 nmol/l).Conclusion:The biochemical phenotype of macro-corticotropinoma resembles that of micro-corticotropinoma despite their larger tumour size, suggesting that the former is relatively less functional. Micro-corticotropinoma ≤6 mm and 6-10 mm have a similar clinical and biochemical profile. As compare to CD, ECS is characterised by a higher disease burden as reflected in their higher cortisol, more autonomicity and loss of rhythmicity.

Ectopic Cushing syndrome presenting as hyperpigmentation

Ectopic Cushing syndrome presenting as hyperpigmentation

Arterial hypertension in rare endocrine pathology: practical observation

The article is devoted to the problem of arterial hypertension due to the rare pathology caused by excessive production of adrenal hormones on the example of its own clinical observations: ectopic ACTH-dependent Cushing's syndrome, primary aldosteronism, androsteroma, pheochromocytoma of the bladder. The issue of timely diagnosis and adequate treatment of these diseases remains one of the urgent tasks of clinical medicine.

Morbidity and mortality in Cushing's syndrome

Endogenous Cushing's syndrome is arare endocrine disorder that is fatal if left untreated. It can be distinguished into adrenocorticotropic hormone (ACTH)-dependent (central and ectopic Cushing's syndrome) and ACTH-independent subtypes (unilateral or bilateral adrenal adenomas). The clinical presentation of patients includes typical stigmata of cortisol excess with physical symptoms of catabolic metabolism (myopathy, striae, parchment skin, osteoporosis) and components of metabolic syndrome (diabetes mellitus, obesity, arterial hypertension, hypercholesterolemia). Biochemical diagnosis is performed in three steps: 1.Confirmation of the diagnosis by 1‑mg dexamethasone suppression test, 24‑h urine free cortisol, and measurement of late-night salivary cortisol. 2.Differentiation of ACTH-dependent Cushing's syndrome from ACTH-independent adrenal Cushing's syndrome by measurement of plasma ACTH. 3.Further subtyping by corticotropin-releasing hormone (CRH) test, inferior petrosal sinus sampling, and imaging modalities. Therapeutic decisions are made on an interdisciplinary basis. First-line therapy for all subtypes is surgery when possible; additional options for all forms include drug therapy and bilateral adrenalectomy. Despite adequate treatment, Cushing's syndrome is associated with increased long-term morbidity and mortality. Interdisciplinary and multimodal therapy management is necessary in the long term to positively influence mortality and reduced quality of life.

Severe Ectopic Cushing's Syndrome: Feasibility of Bilateral Simultaneous Retroperitoneoscopic Adrenalectomy and Risk of Thromboembolic Events

Severe Ectopic Cushing's Syndrome: Feasibility of Bilateral Simultaneous Retroperitoneoscopic Adrenalectomy and Risk of Thromboembolic Events

Medullary thyroid cancer with ectopic Cushing's syndrome: A multicentre case series.

Ectopic Cushing's syndrome (ECS) induced by medullary thyroid cancer (MTC) is rare, and data on clinical characteristics, treatment and outcome are limited. Retrospective cohort study in three German and one Swiss referral centres. Eleven patients with MTC and occurrence of ECS and 22 matched MTC patients without ECS were included. The primary endpoint of this study was the overall survival (OS) in MTC patients with ECS versus 1:2 matched MTC patients without ECS. The median age at diagnosis of ECS was 59 years (range: 35-81) and the median time between initial diagnosis of MTC and diagnosis of ECS was 29 months (range: 0-193). Median serum morning cortisol was 49 µg/dl (range: 17-141, normal range: 6.2-18). Eight (73%) patients received treatment forECS. Treatment of ECS consisted of bilateral adrenalectomy (BADX) in four (36%) patients and adrenostatic treatment in eight (73%) patients. One patient received treatment with multityrosine kinase inhibitor (MKI) to control hypercortisolism. All patients experienced complete resolution of symptoms of Cushing's syndrome and biochemical control of hypercortisolism. Patients with ECS showed a shorter median OS of 87 months (95% confidence interval [95% CI]: 64-111) than matched controls (190 months, 95% CI: 95-285). Of the nine deaths, four were related to progressive disease (PD). Four patients showed PD as well as complications and comorbidities of hypercortisolism before death. This study shows that ECS occurs in advanced stage MTC and is associated with a poor prognosis. Adrenostatic treatment and BADX were effective systemic treatment options in patients with MTC and ECS to control their hypercortisolism. MKI treatment achieved complete remission of hypercortisolism and sustained tumour control in one treated case.

Paraneoplastic cushing’s syndrome: A diagnostic and therapeutic challenge: A case report and literature review

Ectopic Cushing syndrome (ECS) is difficult to diagnose and has a poor prognosis. We report a case of a 44-year-old male who was admitted for clinical suspicion of Cushing’s syndrome. The investigations confirmed the diagnosis of ECS. No tumor was detected in preliminary imaging tests. Then, the octreoscan showed a fixation in a suspect lung node in the middle lobe. The patient was treated initially with medical drugs, he underwent a right middle lobectomy, and yet histopathology did not reveal any nodule. However, the outcome was the healing of our patient. We reviewed published articles to access new diagnostic techniques or advantages in the treatment regimen and a prognosis of ECS. Keywords: ectopic cushing’s syndrome; paraneoplastic syndromes; lung cancer.

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.

Ectopic cushing's syndrome secondary to acinic cell carcinoma of the parotida gland: A case-report

Ectopic cushing's syndrome secondary to acinic cell carcinoma of the parotida gland: A case-report

Ectopic Cushing's syndrome due to advanced medullary thyroid cancer: a case report

Ectopic Cushing's syndrome due to advanced medullary thyroid cancer: a case report

Adrenalectomy in ectopic Cushing's syndrome: A retrospective cohort study from a tertiary care centre.

Neuroendocrine neoplasms (NENs) causing ectopic Cushing's syndrome (ECS) are rare and challenging to treat. In this retrospective cohort study, we aimed to evaluate different approaches for bilateral adrenalectomy (BA) as a treatment option in ECS. Fifty-three patients with ECS caused by a NEN (35 females/18men; mean±SD age: 53±15years) were identified from medical records. Epidemiological and clinical parameters, survival, indications for surgery and timing, as well as duration of surgery, complications and surgical techniques, were collected and further analysed. The primary tumour location was thorax (n=30), pancreas (n=14) or unknown (n=9). BA was performed in 37 patients. Median time from diagnosis of ECS to BA was 2months (range 1-10months). Thirty-two patients received different steroidogenesis inhibitors before BA to control hypercortisolaemia. ECS resolved completely after surgery in 33 patients and severe peri- or postoperative complications were detected in 12 patients. There were fewer severe complications in the endoscopic group compared to open surgery (p=.030). Posterior retroperitoneoscopic BA performed simultaneously by a two surgeon approach had the shortest operating time (p=.001). Despite the frequent use of adrenolytic treatment, BA was necessary in a majority of patients to gain control over ECS. Complication rate was high, probably as a result of the combination of metastatic disease and metabolic disorders caused by high cortisol levels. The two surgeon approach BA may be considered as the method of choice in ECS compared to other BA approaches as a result of fewer complications and a shorter operating time.

Neuroendocrine neoplasia and bone (Review).

This is a narrative review focusing on neuroendocrine neoplasia (NEN) and bone status, in terms of metastases and osteoporosis/fractures. One fifth of NEN have skeletal dissemination, this affinity being regulated by intrinsic tumor factors such as the C-X-C chemokine receptor 4 (CXCR4). Bone colonization impairs the patient quality of life, representing a surrogate of reduced survival. Patients with NEN without bone metastases may exhibit low bone mineral density, perhaps carcinoid-related osteoporosis, yet not a standardized cause of osteoporosis. Case-finding strategies to address bone health in NEN with a good prognosis are lacking. Contributors to fractures in NEN subjects may include: menopausal status and advanced age, different drugs, induced hypogonadism, malnutrition, malabsorption (due to intestinal resection, carcinoid syndrome), hypovitaminosis D, impaired glucose profile (due to excessive hormones such as glucagon, somatostatinoma or use of somatostatin analogues), various corticoid regimes, and high risk of fall due to sarcopenia. Pheocromocytoma/paraganglioma involve bone through malignant forms (bone is an elective site) and potential secondary osteoporosis due to excessive hormonal content and increased sympathetic activity which is a key player of bone microarchitecture/quality as reflected by low Trabecular Bone Score. Glucocorticoid osteoporosis is related to NEN-associated ectopic Cushing syndrome. Currently, there are a lack of studies to emphasis that excessive gut-derivate serotonin in NENs with carcinoid syndrome is a specific activator of bone loss thus a contributor to carcinoid-related osteoporosis.

Somatostatin receptor PET beyond the neuroendocrine tumors of the gastrointestinal tract - the review of literature.

PET of the somatostatine receptors (SSR) is a well-established functional imaging modality in the dia-gnosis of the neuroendocrine tumours (NET) of the gastro-entero-pancreatic origin (GEP). However, it can have a major impact also in other clinical entities. To present a literature review focusing on the effectivity of SSR PET in the dia-gnosis beyond GEP NET. SSR PET provides an accurate dia-gnosis of pulmonary NET, pheochromocytoma and paraganglioma, it may have an important impact on their treatment and clinical management. It allows a detailed estimation of the extent of meningeoma, contributes to precise target volumes for radiotherapy delineation and is sensitive in its residuum or recurrence detection. It can be a valuable method in the syndromes of multiple endocrine neoplasia and in the localization of the source of the ectopic Cushing syndrome. It can be used in the medullary thyroid cancer. An important role of SSR PET lies in the planning and monitoring of the peptide-receptor radionuclide therapy embraced in the theranostic concept.

Endocrine and metabolic disorders in cancer patients

Endocrine and metabolic disorders can occur in the form of paraneoplastic syndrome and as a consequence of oncological treatment. The most common disorders include hypercalcaemia, ectopic production of vasopressin in the course of cancer, ectopic Cushing's syndrome and secondary osteoporosis. What should be taken into account during the diagnosis of endocrine disorders, is paraneoplastic syndrome that frequently precedes the occurrence of symptoms typical of a particular diagnosis, which could influence the proper orientation of the diagnostic process. During and after anticancer treatment, it is recommended that patients should be monitored for the possible development of acute or chronic metabolic and endocrine disorders which may pose a threat to their life or health.

Inferior petrosal sinus sampling and stimulation with CRH: 15 years of experience in a tertiary hospital

BackgroundInferior petrosal sinus sampling (IPSS) is indicated in the diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS), especially when the results of the initial diagnostic tests are discordant. ObjectiveTo describe the patients who underwent this invasive functional test in a tertiary hospital. MethodsThis was an observational study of a retrospective cohort of patients with ACTH-dependent CS and IPSS between 2004 and 2019. We determined their epidemiological, hormonal, radiological and functional characteristics, and evaluated their diagnostic capacity and optimal cut-off points to differentiate between Cushing's disease (CD) and ectopic Cushing's syndrome (ECS). Results23 patients were evaluated, of which 65.2% were women with the average age of 42 (36–62) years. ACTH secretion of pituitary origin was evident in 82.6% of the patients and of ectopic origin in 17.4%. Plasma cortisol, urinary free cortisol, and ACTH levels were higher in patients with ECS. Regarding IPSS, the baseline central/peripheral ACTH gradient detected 89.5% of patients with CD and after stimulation with CRH, 100%. The optimal cut-off points in the diagnosis of CD were 2.06 at baseline and 2.49 after CRH stimulation. ConclusionIPSS with CRH stimulation is a test with a high diagnostic accuracy for correctly classifying patients with CD and ECS. The cut-off points of the gradients may be different from the classic ones. Therefore, we recommend that each center perform its own evaluation.