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BACKGROUND: Adrenocortical carcinoma is a very rare endocrinopathy that has a poor prognosis and is frequently associated with ACTH-independent Cushing's syndrome. Despite having an adrenocortical carcinoma, our patient surprisingly had an ACTH-dependent Cushing's syndrome. CASE REPORT: A 26-year-old female presented with Cushing's syndrome and an abdominal mass. Imaging studies revealed an adrenal mass consistent with a high-grade malignancy. Laboratory workup showed hypercortisolism, hyperandrogenism, and hypokalemia with normal levels of metanephrines. Unexpectedly, her ACTH levels were remarkably elevated. The pathological analysis of a tumor sample was conclusive for adrenocortical carcinoma with immunopositivity for ACTH. CONCLUSIONS: Our patient suffered from an adrenocortical carcinoma that was ectopically producing ACTH. This case emphasizes that physicians should have a broad-minded approach when evaluating cases of rare endocrine malignancies.
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Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Hormona Adrenocorticotrópica , Síndrome de Cushing , Humanos , Femenino , Adulto , Carcinoma Corticosuprarrenal/diagnóstico , Carcinoma Corticosuprarrenal/patología , Carcinoma Corticosuprarrenal/sangre , Neoplasias de la Corteza Suprarrenal/diagnóstico , Neoplasias de la Corteza Suprarrenal/patología , Neoplasias de la Corteza Suprarrenal/sangre , Hormona Adrenocorticotrópica/sangre , Hormona Adrenocorticotrópica/metabolismo , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/etiologíaRESUMEN
Not required for Clinical Vignette.
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Carcinoma Neuroendocrino , Síndrome de Cushing , Neoplasias de la Tiroides , Humanos , Hormona Adrenocorticotrópica , Carcinoma Neuroendocrino/complicaciones , Síndrome de Cushing/etiología , Neoplasias de la Tiroides/complicaciones , Neoplasias de la Tiroides/cirugía , Neoplasias de la Tiroides/patologíaRESUMEN
The cases of 3 patients with Cushing's disease who developed long-term adrenal insufficiency after discontinuation of prolonged osilodrostat therapy were recently described for the first time. We report 2 additional cases of persistent prolonged adrenal insufficiency after discontinuation of osilodrostat treatment for intense hypercortisolism due to Cushing's disease and ectopic ACTH syndrome. In addition, we show for that adrenal insufficiency in these patients was associated with low/normal 11-deoxycortisol concentrations despite high plasma ACTH concentrations. These results suggest that CYP11B1 is not the only target of osilodrostat and that, in vivo, osilodrostat has other prolonged and strong inhibitory effect on adrenal steroidogenesis upstream of CYP11B1. Knowledge of this remnant effect is important for the care of patients with Cushing's syndrome treated with osilodrostat. Further studies are needed to clarify the frequency and the mechanisms of this remnant effect.
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Insuficiencia Suprarrenal , Síndrome de Cushing , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Humanos , Síndrome de Cushing/tratamiento farmacológico , Esteroide 11-beta-Hidroxilasa , Insuficiencia Suprarrenal/tratamiento farmacológico , Insuficiencia Suprarrenal/etiologíaRESUMEN
A previously healthy 11-year-old male was found to have a mass in the pancreatic head after several months of abdominal pain and jaundice. Pathology was consistent with a World Health Organization grade 2 pancreatic neuroendocrine tumor. He developed refractory hypertension and was found to have Cushing syndrome from ectopic ACTH secretion, with oligometastatic liver disease. He underwent surgical resection of the pancreatic tumor and metastases. Postoperatively, his Cushing syndrome resolved, but it reemerged 1 year later in the setting of disease recurrence. He was not a candidate for bilateral adrenalectomy. Ketoconazole therapy was inadequate and he was started on metyrapone, lanreotide, cabergoline, and spironolactone. Although this regimen was well-tolerated, his Cushing syndrome recurred 4 months later as his metastatic disease burden increased. Osilodrostat was begun and the dose was gradually increased in response to his uncontrolled Cushing syndrome. Osilodrostat resulted in rapid improvement and eventual normalization of his urinary free cortisol at a dose of 18â mg twice daily. He had no adverse effects. This rare case highlights the successful off-label use of osilodrostat, a medication intended for refractory Cushing disease in adult patients, in a pediatric patient with Cushing syndrome caused by ectopic ACTH secretion.
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Extra-pituitary ACTH secretion is associated with a variety of neoplastic conditions and may cause the so-called ectopic ACTH-dependent Cushing syndrome (CS). The clarification of the mechanisms of extra-pituitary ACTH expression would provide potential therapeutic targets for this complex and severe disease. In the adenohypophysis, the transcription factor TPIT, co-operating with other molecules, induces POMC expression and ACTH production. However, no data are currently available on the presence and role of TPIT expression in extra-pituitary ACTH-producing neoplasms. This study was designed to explore TPIT expression in a series of pulmonary and pancreatic ACTH-producing tumors, either CS-associated or not. Forty-one extra-pituitary ACTH-producing neuroendocrine tumors (NETs) were included in the study, encompassing 32 NETs of the lung (LuNETs), 7 of the pancreas (PanNETs), and 2 pheochromocytomas. Of these, 9 LuNETs, all PanNETs, and the two pheochromocytomas were CS-associated. For comparison, 6 NETs of the pituitary gland (PitNETs; 3 ACTH-secreting and 3 ACTH-negative) and 35 ACTH-negative extra-pituitary NETs (15 Lu-NETs and 20 PanNETs) were analyzed. Immunohistochemistry with specific anti-TPIT antibodies and quantitative real-time PCR (qRT-PCR) were performed using standard protocols. TPIT expression was completely absent (protein and mRNA) in PanNETs, pheochromocytomas, and all ACTH-negative NETs. In contrast, it was expressed in 16/32 LuNETs, although with lower levels than in PitNETs. No definite relationship was found between immunohistochemistry TPIT expression and NET grade or the presence of Cushing syndrome. This study further highlights the clinical and biological heterogeneity of extra-pituitary ACTH secretion and suggests that the differences between ACTH-secreting PanNETs and LuNETs may mirror distinct molecular mechanisms underlying POMC expression. Our results point towards the recognition of a real corticotroph-like phenotype of ACTH-producing LuNETs, that is not a feature of ACTH-producing PanNETs.
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Neoplasias de las Glándulas Suprarrenales , Carcinoma Neuroendocrino , Síndrome de Cushing , Neoplasias Pulmonares , Tumores Neuroendocrinos , Feocromocitoma , Enfermedades de la Hipófisis , Neoplasias Hipofisarias , Humanos , Hormona Adrenocorticotrópica/metabolismo , Neoplasias Pulmonares/metabolismo , Páncreas/patología , Hipófisis/patología , Neoplasias Hipofisarias/patología , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismoRESUMEN
BACKGROUND: Using machine learning (ML) to explore the noninvasive differential diagnosis of Cushing's disease (CD) and ectopic corticotropin (ACTH) secretion (EAS) model is the next hot research topic. This study was to develop and evaluate ML models for differentially diagnosing CD and EAS in ACTH-dependent Cushing's syndrome (CS). METHODS: Two hundred sixty-four CD and forty-seven EAS were randomly divided into training and validation and test datasets. We applied 8 ML algorithms to select the most suitable model. The diagnostic performance of the optimal model and bilateral petrosal sinus sampling (BIPSS) were compared in the same cohort. RESULTS: Eleven adopted variables included age, gender, BMI, duration of disease, morning cortisol, serum ACTH, 24-h UFC, serum potassium, HDDST, LDDST, and MRI. After model selection, the Random Forest (RF) model had the most extraordinary diagnostic performance, with a ROC AUC of 0.976 ± 0.03, a sensitivity of 98.9% ± 4.4%, and a specificity of 87.9% ± 3.0%. The serum potassium, MRI, and serum ACTH were the top three most important features in the RF model. In the validation dataset, the RF model had an AUC of 0.932, a sensitivity of 95.0%, and a specificity of 71.4%. In the complete dataset, the ROC AUC of the RF model was 0.984 (95% CI 0.950-0.993), which was significantly higher than HDDST and LDDST (both p < 0.001). There was no significant statistical difference in the comparison of ROC AUC between the RF model and BIPSS (baseline ROC AUC 0.988 95% CI 0.983-1.000, after stimulation ROC AUC 0.992 95% CI 0.983-1.000). This diagnostic model was shared as an open-access website. CONCLUSIONS: A machine learning-based model could be a practical noninvasive approach to distinguishing CD and EAS. The diagnostic performance might be close to BIPSS.
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Síndrome de ACTH Ectópico , Síndrome de Cushing , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Humanos , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/diagnóstico , Síndrome de Cushing/diagnóstico , Diagnóstico Diferencial , Síndrome de ACTH Ectópico/diagnóstico , Hormona Adrenocorticotrópica , Muestreo de Seno Petroso , CefdinirRESUMEN
OBJECTIVE: Pneumocystis pneumonia (PcP) is an opportunistic infection occurring in immunocompromised patients. Cushing's syndrome (CS) impairs the immune system, and several authors have reported PcP in patients with CS. The present study aimed to characterize PcP occurring in a CS context and its management in French tertiary centers, in order to highlight the similarities in clinical presentation and treatment according to whether prophylaxis is implemented or not. METHODS: This was a multicenter retrospective study conducted in several French University Hospitals and Cancer Centers. Patients with PcP and confirmed CS regardless of etiology were included. We excluded patients with other known causes of acquired immunodeficiency with increased risk of PcP. RESULTS: Twenty-five patients were included. CS etiology was neoplastic in 84.0% of cases. CS clinical presentation associated predominant catabolic signs (76.0%), hypokalemia (91.7%) and lymphopenia (89.5%). CS was intense in most patients, with mean plasma cortisol levels at diagnosis of 2.424±1.102nmol/L and urinary free cortisol>10× the upper limit of normal in 85.0%. In all patients, PcP onset followed introduction of cortisol blockers, at a median 5.5 days. Patients were treated with 1 to 3 cortisol blockers, mainly metyrapone (88%), which significatively lowered plasma cortisol levels to 667±541nmol/L at the onset of PcP (P<0.001). PcP occurred in 7 patients despite prophylaxis. Finally, 60.0% patients were admitted to intensive care, and 20.0% died of PcP. CONCLUSION: High mortality in patients with PcP implies that clinicians should be better informed about this rare infectious complication. Prophylaxis remains controversial, requiring comparative studies.
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Síndrome de Cushing , Neumonía por Pneumocystis , Humanos , Síndrome de Cushing/complicaciones , Síndrome de Cushing/epidemiología , Síndrome de Cushing/diagnóstico , Estudios Retrospectivos , Neumonía por Pneumocystis/complicaciones , Neumonía por Pneumocystis/epidemiología , Hidrocortisona , Metirapona/uso terapéuticoRESUMEN
CONTEXT: Diagnostic accuracy of testing currently used for the differential diagnosis of Cushing disease (CD) vs ectopic adrenocorticotropic hormone secretion (EAS) is difficult to interpret. OBJECTIVE: The present study aimed to identify and evaluate the diagnostic accuracy of the corticotropin-releasing hormone (CRH) test, the desmopressin test, and the high-dose dexamethasone suppression test (HDDST) when used to establish a CD or EAS diagnosis. METHODS: This study is a systematic review of the literature and meta-analysis. MEDLINE, OVID, and Web of Science databases were searched for articles published between 1990 and 2021. Articles included described at least 1 test(s) (CRH, desmopressin, or HDDST) and the diagnostic reference standard(s) (histopathology, petrosal sinus sampling, surgical remission, imaging, and long-term follow-up) used to establish a CD or EAS diagnosis. RESULTS: Sixty-two studies were included: 43 reported the use of the HDDST; 32, the CRH test; and the 21, the desmopressin test. The CRH test was found to have the highest sensitivity in detecting CD (ACTH 86.9%, 95% CI 82.1-90.6, cortisol 86.2%, 95% CI 78.3-91.5) and the highest specificity in detecting EAS (ACTH 93.9%, 95% CI 87-98.3, cortisol 89.4%, 95% CI 82.8-93.7). This resulted in a high diagnostic odds ratio (58, 95% CI 43.25-77.47), large area under the curve, and a receiver operating characteristic of 0.934. The diagnostic accuracy of the HDDST and desmopressin test was lower than that of the CRH test. CONCLUSION: The meta-analysis indicates that a patient with a positive ACTH response after a CRH test is highly likely to have CD. Further studies analyzing role of dynamic testing in addition to imaging are needed.
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Síndrome de ACTH Ectópico , Síndrome de Cushing , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Humanos , Síndrome de Cushing/diagnóstico , Desamino Arginina Vasopresina , Hidrocortisona , Diagnóstico Diferencial , Síndrome de ACTH Ectópico/diagnóstico , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/diagnóstico , Hormona Adrenocorticotrópica , Hormona Liberadora de CorticotropinaRESUMEN
@#Cushing′s syndrome(CS)is a clinical syndrome caused by a variety of causes, with main manifestations exhibited by central obesity, purple skin striae, hypertension, and diabetes. In patients with adrenocorticotropic hormone(ACTH)-dependent CS, the result of bilateral inferior petrosal sinus sampling(BIPSS)is the gold standard for determining the source of ACTH in the absence of routine imaging findings.However, the indications, contraindications, operating procedures, precautions and outcome judgments of BIPSS differ from one medical center to another, and there are currently no international and domestic clinical guidelines and expert consensus on BIPSS. In order to further improve the operation specifications of BIPSS in the diagnosis process of difficult CS, the Hypothalamic and Pituitary Disease Group of the China Alliance for Rare Diseases and the Innovation Center of Pituitary Diseases of Peking Union Medical College Hospital organized experts in endocrinology, interventional radiology, neurosurgery and laboratory in China to formulate this consensus. This consensus aims to provide standardized methodological guidance for the use of BIPSS in the differential diagnostic process of CS in clinical practice.
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OBJECTIVES: The differential diagnosis of ACTH-dependent Cushing's disease (CS) is challenging. The gold standard approach bilateral inferior petrosal sinus sampling (BIPSS) is expensive and invasive, while other noninvasive tests, like the high-dose dexamethasone suppression test (HDDST), provide unsatisfactory diagnostic accuracy. This study aimed to find a new noninvasive practical approach with higher diagnostic accuracy to differently diagnose ACTH-dependent CS, which can be used in centers where BIPSS cannot be applied. METHODS: 264 Cushing's disease (CD) patients and 47 ectopic ACTH secretion syndrome (EAS) patients were analyzed in this single-center retrospective study (2011-2021). The multivariate logistic model was used to construct the scoring model. RESULTS: Female (adjusted OR 3.030, 95%CI 1.229-7.471), hypokalemia (0.209, 0.076-0.576), ACTH (0.988, 0.982-0.994), MRI pituitary lesion positive (8.671, 3.521-21.352), and HDDST positive (2.768, 1.139-6.726) have a strong association with the differential diagnosis of ACTH-dependent CS and were included in the final multivariable logistic regression model. A -14-to-14-point noninvasive scoring model was built on the model. The AUC of the noninvasive scoring model was 0.915 (95% CI 0.869-0.960), significantly higher than the AUC of HDDST (0.756, 95% CI 0.685-0.825, P = 0.004). The optimal cutoff of the model was ≥0 to diagnose CD. The sensitivity of the noninvasive scoring model was 91.3% (95% CI 87.3%-94.1%), and the specificity was 80.9% (95% CI 67.5%-89.6%). When the model's sensitivity was 100.0%, the cutoff was ≥ -10 with a specificity of 19.2%; when the model's specificity was 100.0%, the cutoff was ≥ 13 with a sensitivity of 22.7%. CONCLUSIONS: We developed a noninvasive scoring model to distinguish CD and EAS in ACTH-dependent CS patients with higher diagnostic utility than HDDST in the same cohort. The noninvasive scoring model might be applied in areas where BIPSS is unavailable, the CRH is hard to obtain, or the desmopressin stimulation is not widely applied. It also provided a triage tool for selecting patients that might benefit the most from a further BIPSS test.
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Síndrome de ACTH Ectópico , Síndrome de Cushing , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Síndrome de ACTH Ectópico/diagnóstico , Hormona Adrenocorticotrópica , Síndrome de Cushing/diagnóstico , Diagnóstico Diferencial , Femenino , Humanos , Muestreo de Seno Petroso , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/diagnóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: Ectopic adrenocorticotropic hormone secretion syndrome occurs in 10% of all patients with adrenocorticotropic-hormone-dependent hypercortisolism. It is usually associated with overt malignancies or with occult and indolent tumors. This study aims to confirm the source of ectopic adrenocorticotropic hormone in four patients with ectopic Cushing's syndrome over time. CASE PRESENTATION: A 38-year-old Iranian man with Cushing's syndrome underwent bilateral adrenalectomy since the source of ectopic adrenocorticotropic hormone secretion was not localized and pituitary imaging was normal. A whole-body scan revealed a right-lung tumoral mass with mediastinal lymph node metastasis. The mass was assumed a lung carcinoid tumor with mediastinal adenopathy. Right-lung mid-zone lobectomy and mediastinal lymphadenectomy were done. In a 47-year-old Iranian man with Cushing's syndrome, whole-body computed tomography scan revealed a pulmonary nodule in the posterior segment of the left lower lobe of the lung. The third case was a 25-year-old Iranian man who presented with symptoms and signs of Cushing's syndrome. Pituitary magnetic resonance imaging revealed a microadenoma 5 × 9 mm. Whole-body scan showed abnormal focal somatostatin receptors analog avid lesion in the posterior aspect of inferior third of right lung, highly suggestive of ectopic adrenocorticotropic-hormone-producing tumor. The last case was a 43-year-old Iranian woman with Marfan syndrome with a history of mitral and aortic valve replacement and chronic dissection of the aorta, who presented with symptoms and signs of Cushing's syndrome. She underwent bilateral adrenalectomy 1 year later owing to failure to locate ectopic adrenocorticotropic hormone syndrome. Whole-body scan showed abnormally increased radiotracer uptake in the midline of the skull base and posterior aspect of the middle zone of left hemithorax and bed of left lobe of thyroid. CONCLUSION: The clinical spectrum of ectopic adrenocorticotropic hormone secretion syndrome is wide, and distinguishing Cushing's disease from ectopic adrenocorticotropic hormone secretion syndrome is difficult. Initial failure to identify a tumor is common. Pulmonary carcinoid or occult source of ectopic adrenocorticotropic hormone secretion syndrome is usually the cause. In occult cases of ectopic adrenocorticotropic hormone in which the tumor cannot be localized, serial follow-up with serial computed tomography, magnetic resonance imaging, or scintigraphy is recommended for several years until the tumor can be localized and treated.
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Síndrome de ACTH Ectópico , Síndrome de Cushing , Síndrome de ACTH Ectópico/cirugía , Adrenalectomía , Adulto , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/cirugía , Femenino , Estudios de Seguimiento , Humanos , Irán , Masculino , Persona de Mediana EdadRESUMEN
In patients with ACTH-dependent Cushing's syndrome (CS), the differentiation between Cushing's disease (CD) and ectopic ACTH secretion (EAS) can often be challenging. The traditionally used biochemical tests have limited diagnostic accuracy and imaging modalities may fail to detect the culprit lesion. Inferior petrosal sinus sampling (IPSS) was introduced more than 3 decades ago as a test with optimal diagnostic accuracy and has since become the gold standard in the differential diagnosis between CD and EAS. However, several, albeit rare, pitfalls may limit its diagnostic accuracy and awareness is needed to avoid incorrect interventions. Moreover, it is an invasive and demanding procedure, available in a limited number of centers worldwide. This review aims to critically present the usefulness and pitfalls of IPSS and define strategies for its optimal place in the contemporary management of CS.
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Síndrome de ACTH Ectópico , Síndrome de Cushing , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Síndrome de ACTH Ectópico/diagnóstico , Hormona Adrenocorticotrópica , Síndrome de Cushing/diagnóstico , Diagnóstico Diferencial , Humanos , Muestreo de Seno Petroso , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/diagnósticoRESUMEN
Cushing's syndrome (CS) is a rare disease caused by chronic and excessive cortisol secretion. When adrenocorticotropin hormone (ACTH) is measurable, autonomous adrenal cortisol secretion could be reasonably ruled out in a differential diagnosis of CS. ACTH-dependent CS accounts for 80%-85% of cases and involves cortisol production stimulated by uncontrolled pituitary or ectopic ACTH secretion. Pituitary adenoma is not detected in up to one-third of cases with pituitary ACTH secretion, whereas cases of CS due to ectopic ACTH secretion may be associated with either malignant neoplasia (such as small cell lung carcinoma) or less aggressive neuroendocrine tumors, exhibiting only the typical symptoms and signs of CS. Since the differential diagnosis of ACTH-dependent CS may be a challenge, many strategies have been proposed. Since none of the available tests show 100% diagnostic accuracy, a step-by-step approach combining several diagnostic tools and a multidisciplinary evaluation in a referral center is suggested. In this review, we present a clinical case to demonstrate the diagnostic work-up of ACTH-dependent CS. We describe the most commonly used dynamic tests, as well as the applications of conventional or nuclear imaging and invasive procedures.
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Síndrome de ACTH Ectópico , Síndrome de Cushing , Síndrome de ACTH Ectópico/diagnóstico , Hormona Adrenocorticotrópica , Síndrome de Cushing/diagnóstico , Diagnóstico Diferencial , Humanos , HidrocortisonaRESUMEN
Knowledge of ectopic Cushing's syndrome (CS) due to thymic neuroendocrine tumours (NETs) comes from short series or single cases. Our aim is to perform a systematic review using PubMed, Embase, Scopus, Ovid Medline and Biosis Previews of all cases with ectopic CS due to thymic NETs reported in the last 40 years and describe one illustrative patient attended in our institution. Search of literature: From 162 patients, 58.6% were male and mean age was 34.6 ± 13.9 years-old. Median of symptoms until diagnosis was 6 [2-24] months and 62% had aggressive CS. Imaging was positive in 93.7% (chest X-ray), 97.8% (computed tomography), 80.7% (somatostatin receptor scintigraphy) and median tumour size was 47 [25-68.5] mm. At presentation, 18% had localized disease, 26.2% locally invasive and 55.7% advanced. Eighty-eight present underwent surgery and histological subtypes were atypical (46.7%), typical (30.4%) and carcinoma (21.7%). Tumour persisted or recurred in 70.1%, 63% received radiotherapy and 45.2% chemotherapy. Follow-up median was 26.6 [14.5-57.5] months and mortality was reported in 35.8% with median survival of 38 [19-60] months. MEN-1 mutation was referred in 3.1%. Comparatively, carcinomas had aggressive CS more frequently while atypical showed advanced disease more often. In conclusion, thymic NETs causing ectopic CS are presented as aggressive hypercortisolism in the middle aged population. The disease is commonly extended at diagnosis and persists or recurs after surgery in most patients with a short term high mortality.
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Síndrome de ACTH Ectópico , Síndrome de Cushing , Tumores Neuroendocrinos , Timoma , Neoplasias del Timo , Síndrome de ACTH Ectópico/complicaciones , Síndrome de ACTH Ectópico/diagnóstico , Síndrome de ACTH Ectópico/cirugía , Adulto , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/etiología , Humanos , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/complicaciones , Timoma/complicaciones , Neoplasias del Timo/diagnóstico , Neoplasias del Timo/patología , Neoplasias del Timo/cirugía , Adulto JovenRESUMEN
Steroidogenesis inhibitors can be given to control the hypercortisolism of Cushing's syndrome in various situations: when surgery has been unsuccessful or not possible; in metastatic adrenocorticotropin hormone (ACTH) or cortisol-secreting tumors; when waiting for the maximal efficacy of radiation techniques; for rapid treatment of severe hypercortisolism in patients with occult ACTH-producing tumors; or as a presurgical treatment in patients with severe comorbidities. Whilst biochemical "control" can be achieved in more than 50% of cases, daily management of such drugs can be challenging. Indeed, with a "dose-titration" or a "block and replace" approach, defining eucortisolism is usually difficult, requiring the measurement of several biological markers. Moreover, each drug has its own side effects, which must be monitored closely. The aim of this "approach to the patient" is to shed light on the management of hypercortisolism with 4 steroidogenesis inhibitors (ketoconazole, levoketoconazole, metyrapone, osilodrostat) to help endocrinologists dealing with patients with Cushing's syndrome. Various points will be discussed, such as initial dose of treatment, dose schedule, monitoring of efficacy, and side effects of monotherapy. The combination of steroidogenesis inhibitors will also be discussed.
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Síndrome de Cushing/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Hormona Adrenocorticotrópica/efectos de los fármacos , Adulto , Femenino , Humanos , Imidazoles/uso terapéutico , Cetoconazol/uso terapéutico , Metirapona/uso terapéutico , Piridinas/uso terapéuticoRESUMEN
OBJECTIVE: Efficacy of bilateral inferior petrosal sinus sampling (BIPSS) in corticotropin-dependent Cushing's syndrome (CS) for localization and lateralization of excess adrenocorticotropic hormone (ACTH) source, as compared to high-dose dexamethasone suppression test (HDDST) and magnetic resonance imaging (MRI) pituitary, respectively. METHODOLOGY: Thirteen patients with clinically and biochemically confirmed CS underwent HDDST, MRI pituitary, and BIPSS by an experienced team of intervention neurologist, neurosurgeon, and endocrinologist using percutaneous femoral vein approach. RESULTS: Of 13 patients (11 adults and two children) who underwent BIPSS, raised central to peripheral ACTH ratio was achieved in 12 cases, remaining one case being ectopic ACTH secretion (EAS). However, inter IPS gradient >1.4 was achieved in 11 (91.6%) of 12 Cushing's disease (CD) cases before vasopressin stimulation; and in 9 (75%) of 12 CD cases after vasopressin stimulation (P-value 0.583). HDDST suppression of more than 50% was present in only ten cases with CD, falsely negating CD in two cases (16.6%), sensitivity 83.3% and specificity 100%. MRI sella demonstrated pituitary microadenoma in 12 cases and macroadenoma in one case. Lateralization by BIPSS and MRI was concordant in 7 (58.3%) out of 12 cases with CD, with rate of remission after transsphenoidal surgery being higher in patients with concordant lateralization by BIPSS and MRI. CONCLUSIONS: BIPSS is an important investigation to distinguish CD and EAS. BIPSS was superior to HDDST for confirming the source of excess ACTH. Our findings favor the use of BIPSS for localization and pituitary MRI for lateralization of microadenoma.
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CONTEXT: The human corticotropin-releasing hormone (CRH) test (hCRHtest) is used to differentiate Cushing disease (CD) from ectopic adrenocorticotropin (ACTH) secretion (EAS), to assess autonomous cortisol secretion by the adrenal glands, and to characterize pseudo-Cushing syndrome (CS) or adrenal insufficiency (AI). MAIN OUTCOME MEASURE: The main outcome measure of this study was to assess the diagnostic accuracy of the hCRHtest. METHODS: We measured ACTH and cortisol levels; collected the peak values (peakACTH and peakcortisol), and calculated the percentage increases (∆%ACTH and ∆%cortisol) after an intravenous bolus of 100 µg hCRH. DESIGN AND SETTING: This cross-sectional study of hCRH tests from 2010 to 2019 took place in a referral university hospital center. PATIENTS: We enrolled 200 patients: 86 CD, 15 EAS, 18 adrenal CS, 25 mild adrenal autonomous cortisol secretion, 31 pseudo-CS, and 25 suspected AI. RESULTS: The hCRHtest was performed mainly for the differential diagnosis of ACTH-dependent CS or adrenal lesions (P = .048). PeakACTH and peakcortisol were higher in CD, and ∆%ACTH and ∆%cortisol were able to differentiate CD from EAS with a sensitivity and specificity greater than 80%. In patients with low (<â 10 pg/mL) or indeterminate (10-20 pg/mL) basalACTH levels, an absent or reduced peakACTH response was able to differentiate adrenal from ACTH-dependent forms. PeakACTH and peakcortisol after hCRHtest were lower in pseudo-CS than in CD, but ∆%ACTH and ∆%cortisol were similar. The role of hCRHtest in patients with AI was limited. CONCLUSIONS: The hCRHtest test is the mainstay of the differential diagnosis of ACTH-dependent CS. It is also useful for pointing to a diagnosis of CD in the event of bilateral adrenal masses, and in patients with low basalACTH.
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Síndrome de ACTH Ectópico/diagnóstico , Insuficiencia Suprarrenal/diagnóstico , Hormona Adrenocorticotrópica/sangre , Hormona Liberadora de Corticotropina , Hidrocortisona/sangre , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/diagnóstico , Síndrome de ACTH Ectópico/sangre , Insuficiencia Suprarrenal/sangre , Adulto , Estudios Transversales , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/sangre , Pruebas de Función Hipofisaria , Pruebas de Función Adreno-Hipofisaria , Sensibilidad y EspecificidadRESUMEN
OBJECTIVES: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: [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.
Asunto(s)
Hormona Adrenocorticotrópica/metabolismo , Síndrome de Cushing/terapia , Tumores Neuroendocrinos/terapia , Compuestos Organometálicos/metabolismo , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Adulto , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/diagnóstico por imagen , Femenino , Estudios de Seguimiento , Radioisótopos de Galio/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/metabolismo , Derivación y Consulta/estadística & datos numéricos , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
INTRODUCTION: Ectopic Cushing's syndrome (ECS) is a rare condition caused by ACTH secretion by extrapituitary tumors. Its low frequency makes it difficult to acquire experience in its management. The aim of this study was to describe patients with ECS seen at the endocrinology department of a tertiary hospital over 15 years. METHODS: This was a retrospective study of the clinical, biochemical and radiographic data, treatment, and course of patients with ECS seen from 2000 to 2015. RESULTS: Nine patients (6 of them female) with a mean age of 47 years were included in the study. The clinical syndrome developed in less than 3 months in all cases but one, and most patients also had edema, hyperpigmentation and/or hypokalemia. Mean urinary free cortisol and ACTH levels were 2,840µg/24h and 204pg/mL respectively. The ectopic origin was confirmed by a combination of dynamic non-invasive tests and radiographic studies in most cases. The tumor responsible could be identified in 8 cases, and 7 patients had metastatic dissemination. Primary treatment was surgery in one patient, surgery combined with systemic therapy in 3, and chemotherapy in the other 3 patients. Bilateral adrenalectomy was required in 4 patients to control hypercortisolism. After a mean follow-up of 40 months, 3 patients died, 5 were still alive, and one had been lost to follow-up. CONCLUSIONS: Our study confirms that ECS covers a wide spectrum of tumors of different aggressiveness and nature. The ectopic origin of Cushing's syndrome can usually, be suspected and confirmed in most cases without the need for invasive tests. Control of both hypercortisolism and the tumor requires multiple treatment modalities, and multidisciplinary management is recommended.
Asunto(s)
Síndrome de ACTH Ectópico/complicaciones , Síndrome de Cushing/etiología , Neoplasias Pancreáticas/complicaciones , Síndrome de ACTH Ectópico/tratamiento farmacológico , Síndrome de ACTH Ectópico/cirugía , Neoplasias de las Glándulas Suprarrenales/complicaciones , Neoplasias de las Glándulas Suprarrenales/cirugía , Adrenalectomía , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Tumor Carcinoide/complicaciones , Tumor Carcinoide/tratamiento farmacológico , Tumor Carcinoide/secundario , Tumor Carcinoide/cirugía , Carcinoma de Células Pequeñas/complicaciones , Carcinoma de Células Pequeñas/secundario , Carcinoma de Células Pequeñas/cirugía , Terapia Combinada , Femenino , Gastrinoma/complicaciones , Gastrinoma/diagnóstico , Gastrinoma/tratamiento farmacológico , Gastrinoma/secundario , Humanos , Hidrocortisona/orina , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/cirugía , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/cirugía , Feocromocitoma/complicaciones , Feocromocitoma/cirugía , Estudios Retrospectivos , Neoplasias Gástricas/complicaciones , Neoplasias del Timo/complicaciones , Neoplasias del Timo/tratamiento farmacológico , Neoplasias del Timo/cirugía , Adulto JovenRESUMEN
OBJECTIVES: Paraneoplastic Cushing syndrome is a rare condition, representing a small fraction of the adrenocorticotropic hormone (ACTH)-dependent cases of Cushing syndrome Methods: Four case descriptions and literature review, highlighting the diagnostic challenges and treatment options are presented. RESULTS: Different tumor types can be associated with ectopic ACTH secretion. The most common types are bronchial carcinoids and small cell lung carcinoma (SCLC). However, in approximately 10 to 20% of the cases, no overt tumor (occult tumor) can be found. The diagnosis is made in a multistep process. Firstly, hypercortisolemia and adrenocorticotropin hormone dependency have to be confirmed. Distinction between a pituitary or ectopic cause can be cumbersome. MRI of the pituitary gland, a corticotropin releasing hormone stimulation test and a sinus petrosus sampling can be used. Treatment options consist of tumor management, somatostatin analogs, steroidogenesis inhibitors, and bilateral adrenalectomy. CONCLUSION: Clinicians should consider the diagnosis, and opt for specific treatment, especially in patients with a history of neuroendocrine tumors.