RESUMEN
Ectopic Cushing's syndrome due to ectopic ACTH&CRH-secreting by pheochromocytoma is extremely rare and can be fatal if not properly diagnosed. It remains unclear whether a unique cell type is responsible for multiple hormones secreting. In this work, we performed single-cell RNA sequencing to three different anatomic tumor tissues and one peritumoral tissue based on a rare case with ectopic ACTH&CRH-secreting pheochromocytoma. And in addition to that, three adrenal tumor specimens from common pheochromocytoma and adrenocortical adenomas were also involved in the comparison of tumor cellular heterogeneity. A total of 16 cell types in the tumor microenvironment were identified by unbiased cell clustering of single-cell transcriptomic profiles from all specimens. Notably, we identified a novel multi-functionally chromaffin-like cell type with high expression of both POMC (the precursor of ACTH) and CRH, called ACTH+&CRH + pheochromocyte. We hypothesized that the molecular mechanism of the rare case harbor Cushing's syndrome is due to the identified novel tumor cell type, that is, the secretion of ACTH had a direct effect on the adrenal gland to produce cortisol, while the secretion of CRH can indirectly stimulate the secretion of ACTH from the anterior pituitary. Besides, a new potential marker (GAL) co-expressed with ACTH and CRH might be involved in the regulation of ACTH secretion. The immunohistochemistry results confirmed its multi-functionally chromaffin-like properties with positive staining for CRH, POMC, ACTH, GAL, TH, and CgA. Our findings also proved to some extent the heterogeneity of endothelial and immune microenvironment in different adrenal tumor subtypes.
Asunto(s)
Síndrome de ACTH Ectópico/diagnóstico , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Feocromocitoma/diagnóstico , Transcriptoma , Síndrome de ACTH Ectópico/metabolismo , Síndrome de ACTH Ectópico/patología , Neoplasias de las Glándulas Suprarrenales/metabolismo , Neoplasias de las Glándulas Suprarrenales/patología , Hormona Adrenocorticotrópica/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Perfilación de la Expresión Génica , Feocromocitoma/metabolismo , Feocromocitoma/patología , Análisis de la Célula IndividualRESUMEN
The management of endogenous Cushing's syndrome (CS) typically involves two key steps: (i) confirmation of autonomous hypercortisolism and (ii) localization of the cause to guide treatment. Adrenocorticotropic hormone (ACTH)-dependent CS is most commonly due to a pituitary corticotrope tumor which may be so small as to evade detection on conventional magnetic resonance imaging (MRI). Although biochemical testing (e.g., corticotropin stimulation; dexamethasone suppression) can provide an indication of the likely origin of ACTH excess, bilateral inferior petrosal sinus catheterization offers greater accuracy to distinguish pituitary-driven CS [Cushing's Disease (CD)] from the ectopic ACTH syndrome [EAS, e.g., due to a bronchial or pancreatic neuroendocrine tumor (NET)]. In patients with CD, 40-50% may not have a pituitary adenoma (PA) readily visualized on standard clinical MRI. In these subjects, alternative MR sequences (e.g., dynamic, volumetric, fluid attenuation inversion recovery) and higher magnetic field strength (7T > 3T > 1.5T) may aid tumor localization but carry a risk of identifying coincidental (non-causative) pituitary lesions. Molecular imaging is therefore increasingly being deployed to detect small ACTH-secreting PA, with hybrid imaging [e.g., positron emission tomography (PET) combined with MRI] allowing precise anatomical localization of sites of radiotracer (e.g., 11C-methionine) uptake. Similarly, small ACTH-secreting NETs, missed on initial cross-sectional imaging, may be detected using PET tracers targeting abnormal glucose metabolism (e.g., 18F-fluorodeoxyglucose), somatostatin receptor (SSTR) expression (e.g., 68Ga-DOTATATE), amine precursor (e.g., 18F-DOPA) or amino acid (e.g., 11C-methionine) uptake. Therefore, modern management of ACTH-dependent CS should ideally be undertaken in specialist centers which have an array of cross-sectional and functional imaging techniques at their disposal.
Asunto(s)
Síndrome de ACTH Ectópico/diagnóstico , Síndrome de Cushing/diagnóstico , Diagnóstico por Imagen/tendencias , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/diagnóstico , Síndrome de ACTH Ectópico/complicaciones , Síndrome de ACTH Ectópico/metabolismo , Adenoma Hipofisario Secretor de ACTH/complicaciones , Adenoma Hipofisario Secretor de ACTH/diagnóstico , Adenoma Hipofisario Secretor de ACTH/metabolismo , Adenoma/complicaciones , Adenoma/diagnóstico , Adenoma/metabolismo , Hormona Adrenocorticotrópica/metabolismo , Síndrome de Cushing/etiología , Síndrome de Cushing/metabolismo , Diagnóstico Diferencial , Diagnóstico por Imagen/clasificación , Diagnóstico por Imagen/métodos , Técnicas de Diagnóstico Endocrino/clasificación , Técnicas de Diagnóstico Endocrino/tendencias , Humanos , Invenciones , Imagen por Resonancia Magnética , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/metabolismo , Hipófisis/diagnóstico por imagen , Hipófisis/metabolismo , Tomografía de Emisión de PositronesRESUMEN
OBJECTIVE: Hair cortisol (HF) and cortisone (HE) measurements reflect tissular exposure to cortisol over months and are increased in overt Cushing's syndrome (CS). No data is available in mild CS. We compared the diagnostic performance of HF and HE between patients with overt or mild CS. DESIGN: Single centre retrospective study. METHODS: HF&HE were measured by LC-MS/MS in 48 consecutive adult females with Cushing's disease (CD), ectopic ACTH syndrome, secreting adenomas and carcinomas, and adrenal incidentalomas. All had impaired dexamethasone suppression tests. Overt CS (n = 25) was diagnosed in front of specific symptoms, a mean UFC (>1.5 ULN) and increased midnight serum cortisol or salivary cortisol. Mild CS (n = 23) was diagnosed in patients lacking specific symptoms and displaying at least one additional biological abnormality including mildly increased UFC (≤1.5 ULN), increased midnight serum cortisol or salivary cortisol and suppressed plasma ACTH in patients with adrenal tumours. In this study, 84 healthy subjects and obese patients served as controls. RESULTS: HF and HE showed roughly similar performance in overt CS (92 and 100% sensitivity, 91 and 99% specificity, respectively). HF and HE were lower in mild CS but higher than in controls (P < 0.01). HE was correlated with midnight serum cortisol (P < 0.02) and volume of adrenal incidentalomas (P < 0.04) but not with UFC. HF and HE had 59% and 68% sensitivity, and 79 and 94% specificity, respectively, for the diagnosis of mild CS. Contrary to UFC, both HF and HE were in the range of overt CS in 11/23 patients with mild CS. Patients with mild CS and increased HE required more antihypertensive treatments and showed worser lipid profiles than patients with normal HE. CONCLUSIONS: HF and HE measurement performed better in overt than in mild CS but is a useful adjunct to diagnose mild CS and to identify adrenocortical incidentalomas responsible for excessive cortisol exposure.
Asunto(s)
Cortisona/análisis , Síndrome de Cushing/diagnóstico , Técnicas de Diagnóstico Endocrino , Cabello/química , Hidrocortisona/análisis , Síndrome de ACTH Ectópico/diagnóstico , Síndrome de ACTH Ectópico/metabolismo , Adenoma/diagnóstico , Adenoma/metabolismo , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/metabolismo , Adulto , Anciano , Estudios de Casos y Controles , Cortisona/metabolismo , Síndrome de Cushing/metabolismo , Síndrome de Cushing/patología , Femenino , Cabello/metabolismo , Humanos , Hidrocortisona/metabolismo , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Sensibilidad y Especificidad , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Corticotrophin-releasing hormone (CRH) is the major regulator of adrenocorticotrophic hormone (ACTH) secretion from the anterior pituitary and acts via CRH-1 receptors (CRH-1R). Corticotropinoma though autonomous, still retain their responsiveness to CRH and hence, we hypothesize that in vivo detection of CRH-1 receptors on pituitary adenoma using Gallium-68 (68Ga)-tagged CRH can indicate the functionality of adenoma, and combining it with positron emission tomography-computed tomography (PET-CT) can provide requisite anatomical information. METHODS: Subjects with ACTH-dependent Cushing's syndrome (CS) (n = 27, 24 with Cushing's disease [CD], 3 with ectopic CS [ECS]) underwent 68Ga CRH PET-CT. Two nuclear medicine physicians read these images for adenoma delineation and superimposed them on magnetic resonance imaging (MRI) sella. The information provided was used for intraoperative navigation and compared with operative and histopathological findings. FINDINGS: 68Ga CRH PET-CT correctly delineated corticotropinoma in all the 24 cases of CD, including the 10 cases with adenoma size < 6mm (4 cases were negative on MRI). Corticotropinoma location on 68Ga CRH PET fusion images with MRI were concordant with operative findings and were further confirmed on histopathology. There was no tracer uptake in the pituitary in 2 patients with ECS, while, in another, the diffuse uptake in pituitary suggested ectopic CRH production. CONCLUSION: 68Ga CRH PET-CT represents a novel, noninvasive molecular imaging, targeting CRH receptors that not only delineate corticotropinoma and provides the surgeon with valuable information for intraoperative tumor navigation, but also helps in differentiating a pituitary from an extra-pituitary source of ACTH-dependent CS. FUNDING: None.
Asunto(s)
Adenoma Hipofisario Secretor de ACTH/diagnóstico , Adenoma/diagnóstico , Imagen Molecular/métodos , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Síndrome de ACTH Ectópico/diagnóstico , Síndrome de ACTH Ectópico/metabolismo , Adenoma Hipofisario Secretor de ACTH/metabolismo , Adenoma Hipofisario Secretor de ACTH/patología , Adenoma/metabolismo , Adenoma/patología , Adolescente , Hormona Adrenocorticotrópica/análisis , Hormona Adrenocorticotrópica/metabolismo , Adulto , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/metabolismo , Síndrome de Cushing/patología , Diagnóstico Diferencial , Femenino , Radioisótopos de Galio , Humanos , India , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Muestreo de Seno Petroso , Receptores de Hormona Liberadora de Corticotropina/análisis , Adulto JovenRESUMEN
Cushing's disease caused due to adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (ACTHomas) leads to hypercortisolemia, resulting in increased morbidity and mortality. Autonomous ACTH secretion is attributed to the impaired glucocorticoid negative feedback (glucocorticoid resistance) response. Interestingly, other conditions, such as ectopic ACTH syndrome (EAS) and non-neoplastic hypercortisolemia (NNH, also known as pseudo-Cushing's syndrome) also exhibit glucocorticoid resistance. Therefore, to differentiate between these conditions, several dynamic tests, including those with desmopressin (DDAVP), corticotrophin-releasing hormone (CRH), and Dex/CRH have been developed. In normal pituitary corticotrophs, ACTH synthesis and secretion are regulated mainly by CRH and glucocorticoids, which are the ACTH secretion-stimulating and -suppressing factors, respectively. These factors regulate ACTH synthesis and secretion through genomic and non-genomic mechanisms. Conversely, glucocorticoid negative feedback is impaired in ACTHomas, which could be due to the overexpression of 11ß-HSD2, HSP90, or TR4, or loss of expression of CABLES1 or nuclear BRG1 proteins. Genetic analysis has indicated the involvement of several genes in the etiology of ACTHomas, including USP8, USP48, BRAF, and TP53. However, the association between glucocorticoid resistance and these genes remains unclear. Here, we review the clinical aspects and molecular mechanisms of ACTHomas and compare them to those of other related conditions.
Asunto(s)
Hormona Adrenocorticotrópica/biosíntesis , Síndrome de Cushing/etiología , Síndrome de Cushing/metabolismo , Susceptibilidad a Enfermedades , Síndrome de ACTH Ectópico/diagnóstico , Síndrome de ACTH Ectópico/etiología , Síndrome de ACTH Ectópico/metabolismo , Adenoma Hipofisario Secretor de ACTH/diagnóstico , Adenoma Hipofisario Secretor de ACTH/etiología , Adenoma Hipofisario Secretor de ACTH/metabolismo , Hormona Adrenocorticotrópica/genética , Biomarcadores , Síndrome de Cushing/diagnóstico , Diagnóstico Diferencial , Femenino , Regulación de la Expresión Génica , Glucocorticoides/metabolismo , Humanos , Masculino , Transducción de SeñalRESUMEN
OBJECTIVE: Pancreatic neuroendocrine tumors (pNETs) causing ectopic adrenal corticotropic hormone (ACTH) syndrome (EAS) are rare and aggressive with little known information. We aimed to elucidate the clinical features and molecular mechanisms of pNETs with EAS by methylation analysis. METHODS: Seven patients with ectopic ACTH-secreting pNETs who were diagnosed at Shanghai Clinical Endocrine and Metabolic Diseases Center and Pancreatic Disease Center in Ruijin Hospital between 2001 and 2019 were enrolled. Twenty patients with ectopic ACTH-secreting thymic neuroendocrine tumors (TNETs) and 7 with nonfunctional pNETs (nf-pNETs) were also enrolled as controls. We collected clinical data and measured POMC promoter CpG methylation. RESULTS: All 7 patients had elevated ACTH and urinary free cortisol (UFC) levels with positive ACTH staining in the pancreas and were diagnosed with ectopic ACTH-secreting pNET. Of the 7 patients, 6 underwent surgery and 1 underwent transarterial embolization (TAE). Two patients were free of disease after surgery; 2 died within 90 days after surgery; and 3 had metastases and died within 1 year. Compared with ACTH-secreting TNETs, ACTH-secreting pNETs had similar clinical and biochemical features but a significantly poorer prognosis. POMC promoter CpG methylation was significantly lower in ACTH-secreting pNETs than in nf-pNETs and normal pancreas. CONCLUSIONS: ACTH-secreting pNETs are aggressive and fatal. Surgery is definitively curative for patients with resectable primary tumors without metastasis. Pro-opiomelanocortin (POMC) promoter hypomethylation caused pNETs to produce ACTH. This study further supplements the genetic features of ACTH-secreting NETs.
Asunto(s)
Síndrome de ACTH Ectópico/metabolismo , Hormona Adrenocorticotrópica/metabolismo , Tumores Neuroendocrinos/metabolismo , Neoplasias Pancreáticas/metabolismo , Síndrome de ACTH Ectópico/etiología , Síndrome de ACTH Ectópico/patología , Síndrome de ACTH Ectópico/cirugía , Adulto , Metilación de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/complicaciones , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/cirugía , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , Regiones Promotoras Genéticas , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Adrenal lipid-poor adenomas (LPA) are defined by high unenhanced density (≥ 10 HU), and absolute and relative contrast medium washout > 60% and > 40%, respectively, at computerized tomography (CT). To date, no thorough histopathological characterization has been performed in those frequent lesions (one-third of adrenal adenomas). Our aim was to analyze the histopathological characteristics of adrenal LPA. METHODS: Patients with LPA (n = 57) were selected among consecutive subjects referred for an adrenal incidentaloma or ACTH-independent Cushing syndrome. FluoroDeoxyGlucose-Positron Emission Tomography (FDG-PET) was performed in 37 patients. In patients treated by adrenalectomy (n = 17), Weiss score and Lin-Weiss-Bisceglia score (in tumors composed entirely or predominantly of oncocytes) were calculated. RESULTS: Radiological parameters did not differ among patients with ACTH-independent Cushing syndrome (n = 6) and those with adrenal incidentalomas associated with primary aldosteronism (n = 2), autonomous cortisol secretion (n = 14), or non-functioning (n = 35). Patients treated by adrenalectomy had larger tumors (28.9 ± 11.2 vs 17.3 ± 8.4 mm, P < 0.001), higher CT unenhanced density (29.1 ± 11.0 vs 23.1 ± 9.0 HU, P = 0.043), and FDG-PET adrenal uptake (9.0 ± 6.4 vs 4.4 ± 2.3 SUV, P = 0.003) than non-operated ones. Oncocytic features > 75% of the tumor were detected in 12/17 cases (70.6%). Five of those showed borderline-malignant histopathological characteristics by Lin-Weiss-Bisceglia score. Among remaining non-oncocytic tumors, 1/5 had a Weiss score ≥ 3. Overall, 6/17 tumors (35.3%) had borderline-malignant potential. Radiological parameters were similar between patients with benign and borderline-malignant tumors. CONCLUSIONS: Adrenal LPA are a heterogeneous group of tumors, mostly composed of oncocytomas. Up to 1/3 of those tumors may have a borderline-malignant potential at histopathology.
Asunto(s)
Adenoma/diagnóstico , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Síndrome de ACTH Ectópico/diagnóstico , Síndrome de ACTH Ectópico/etiología , Síndrome de ACTH Ectópico/metabolismo , Síndrome de ACTH Ectópico/patología , Adenoma/metabolismo , Adenoma/patología , Neoplasias de las Glándulas Suprarrenales/metabolismo , Neoplasias de las Glándulas Suprarrenales/patología , Hormona Adrenocorticotrópica/metabolismo , Adulto , Anciano , Biopsia , Estudios de Cohortes , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/etiología , Síndrome de Cushing/metabolismo , Síndrome de Cushing/patología , Femenino , Fluorodesoxiglucosa F18 , Humanos , Italia , Metabolismo de los Lípidos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Tomografía Computarizada por Rayos XRESUMEN
Steroid cell tumors occur usually in the ovaries with very few reported cases of extra-ovarian origin. Our patient was a fifteen year old female, complaining from secondary amenorrhea and voice deepening. Values of serum cortisol, DHEA, FSH & LH were normal. Serum Testosterone was elevated while ACTH-pm was markedly elevated. MRI described bilateral solid para-ovarian masses. Exploration revealed two bilateral tubal extraluminal cysts & a right broad ligament cyst which were all excised. Pathological examination led to the diagnosis of steroid cell tumor. Serum testosterone & ACTH returned to normal levels after surgery with subsequent regression of the virilizing symptoms. We can conclude that extra-ovarian steroid cell tumors are extremely rare. They are usually presented with virilizing symptoms and hormonal abnormalities. Surgery is the main line of treatment.
Asunto(s)
Síndrome de ACTH Ectópico/diagnóstico , Ligamento Ancho/patología , Neoplasias de las Trompas Uterinas/diagnóstico , Neoplasias Pélvicas/diagnóstico , Tumores de los Cordones Sexuales y Estroma de las Gónadas/diagnóstico , Síndrome de ACTH Ectópico/etiología , Síndrome de ACTH Ectópico/metabolismo , Adolescente , Hormona Adrenocorticotrópica/metabolismo , Ligamento Ancho/metabolismo , Egipto , Neoplasias de las Trompas Uterinas/complicaciones , Neoplasias de las Trompas Uterinas/metabolismo , Neoplasias de las Trompas Uterinas/patología , Femenino , Humanos , Neoplasias Pélvicas/complicaciones , Neoplasias Pélvicas/metabolismo , Neoplasias Pélvicas/patología , Tumores de los Cordones Sexuales y Estroma de las Gónadas/complicaciones , Tumores de los Cordones Sexuales y Estroma de las Gónadas/metabolismo , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Virilismo/diagnóstico , Virilismo/etiología , Virilismo/metabolismoRESUMEN
PURPOSE: We investigated the expression of vasopressin receptor 2 and 3 on corticotrophin tumor cells, their role in regulating ACTH secretion, and their potential therapeutic implications. METHODS: We retrospectively assessed 52 hospitalized patients with pathologically confirmed ACTH-secreting tumors. The expression of vasopressin receptor 2 and 3 was explored via qualitative and quantitative immunohistochemistry analyses. The role of vasopressin receptors in regulating ACTH secretion was further studied in the AtT-20 cell line. RESULTS: Among 50 cases of pituitary corticotrophin adenoma, 31 were vasopressin receptor 2 positive, 38 were vasopressin receptor 3 positive, and 24 were both vasopressin receptor 2 and 3 positive. Two patients with ectopic ACTH syndrome were vasopressin receptor 3 positive, and one was also vasopressin receptor 2 positive. In 12 patients who underwent bilateral inferior petrosal sinus sampling before surgery, the central ACTH increment ratio after desmopressin stimulation was correlated with vasopressin receptor 2 but not with vasopressin receptor 3 staining intensity. In an in vitro study, the expression of both vasopressin receptor 2 and 3 on AtT-20 cells was confirmed. The vasopressin receptor 2 antagonist Tolvaptan inhibited desmopressin-induced ACTH secretion in a dose-dependent manner. CONCLUSIONS: Both vasopressin receptor 2 and 3 are expressed in ACTH-secreting tumors. Vasopressin receptor 2 rather than vasopressin receptor 3 is the primary receptor that seems to mediate the ACTH response in corticotrophin tumors. A vasopressin receptor 2 antagonist can inhibit ACTH secretion induced by desmopressin in AtT-20 cells.
Asunto(s)
Síndrome de ACTH Ectópico/metabolismo , Hormona Adrenocorticotrópica/metabolismo , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacología , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/metabolismo , Receptores de Vasopresinas/metabolismo , Adolescente , Hormona Adrenocorticotrópica/efectos de los fármacos , Adulto , Línea Celular Tumoral , Desamino Arginina Vasopresina/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/metabolismo , Adulto JovenRESUMEN
Ectopic ACTH syndrome (EAS) due to a prostate small cell carcinoma (SCC) is very rare with only 26 cases reported to date and has a poor prognosis. We here describe another case of this disorder that was clinically typical based on prior reports as it showed hypercortisolemia and severe hypokalemia with multiple metastasis. However, our current case of prostate SCC causing EAS is the first to display negative immunostaining for ACTH despite detectable POMC mRNA expression in the primary lesion. ACTH immunonegativity is thought to be associated with a more aggressive disease course and a poorer prognosis although there are few studies of the underlying mechanisms. We explored two possibilities for this finding in our current patient: aberrant POMC processing prevented immunodetection with an anti-ACTH antibody; and the ACTH content per cell was below the threshold for immunodetection due to its rapid secretion or low synthesis. The aberrant processing theory was thought to be less likely because of immunonegative findings even using anti-POMC/ACTH antibodies. As the plasma ACTH levels in our patient were comparable with those reported for previous immunopositive prostate EAS cases, we speculated that the depletion of ACTH may be caused not only by rapid secretion but also by low production levels as a sign of de-differentiation. De-differentiation may therefore explain the mechanism underlying the negative correlation between immunoreactivity for ACTH in EAS and disease aggressiveness. We believe that our present findings will be of use in future prospective studies aimed at confirming the mechanism of immunonegativity.
Asunto(s)
Síndrome de ACTH Ectópico/etiología , Carcinoma de Células Pequeñas/complicaciones , Próstata/metabolismo , Neoplasias de la Próstata/complicaciones , Síndrome de ACTH Ectópico/metabolismo , Síndrome de ACTH Ectópico/patología , Hormona Adrenocorticotrópica/sangre , Anciano , Carcinoma de Células Pequeñas/metabolismo , Carcinoma de Células Pequeñas/patología , Humanos , Masculino , Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patologíaAsunto(s)
Síndrome de ACTH Ectópico/complicaciones , Neoplasias de las Glándulas Suprarrenales/complicaciones , Hipopotasemia/etiología , Feocromocitoma/complicaciones , Taquicardia/etiología , Síndrome de ACTH Ectópico/diagnóstico , Síndrome de ACTH Ectópico/metabolismo , Síndrome de ACTH Ectópico/fisiopatología , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/metabolismo , Neoplasias de las Glándulas Suprarrenales/fisiopatología , Hormona Adrenocorticotrópica/metabolismo , Anciano , Alcalosis/diagnóstico , Alcalosis/etiología , Bloqueo de Rama/complicaciones , Cardioversión Eléctrica , Electrocardiografía , Humanos , Hipopotasemia/tratamiento farmacológico , Hipopotasemia/metabolismo , Masculino , Feocromocitoma/diagnóstico , Feocromocitoma/metabolismo , Feocromocitoma/fisiopatología , Taquicardia/diagnóstico , Taquicardia/metabolismo , Taquicardia/fisiopatología , Fibrilación Ventricular/etiología , Fibrilación Ventricular/terapiaAsunto(s)
Síndrome de ACTH Ectópico/diagnóstico , Tumor Carcinoide/secundario , Neoplasias Pulmonares/secundario , Síndrome de ACTH Ectópico/tratamiento farmacológico , Síndrome de ACTH Ectópico/metabolismo , Hormona Adrenocorticotrópica/metabolismo , Anciano , Tumor Carcinoide/tratamiento farmacológico , Tumor Carcinoide/metabolismo , Everolimus/uso terapéutico , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismoRESUMEN
Despite modern imaging techniques, differentiating ectopic adrenocorticotropic hormone (ACTH) syndrome from pituitary-dependent Cushing's syndrome, Cushing's disease, is especially difficult when well-differentiated carcinoids are the source of ACTH secretion, particularly pulmonary carcinoid tumors. ACTH-secreting pulmonary carcinoids, like the corticotroph adenomas causing Cushing's disease, are often small and difficult to detect, and patients present with a gradual onset of the classical signs and symptoms of Cushing's syndrome, indistinguishable from the presentation of Cushing's disease. Hence, the differential diagnosis relies on a combination of clinical assessment, dynamic biochemical tests, inferior petrosal sinus sampling, and multimodal imaging, each with its own caveats and pitfalls.
Asunto(s)
Síndrome de ACTH Ectópico , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/diagnóstico , Síndrome de ACTH Ectópico/diagnóstico , Síndrome de ACTH Ectópico/tratamiento farmacológico , Síndrome de ACTH Ectópico/metabolismo , Síndrome de ACTH Ectópico/cirugía , HumanosAsunto(s)
Síndrome de ACTH Ectópico/diagnóstico , Carcinoma Neuroendocrino/diagnóstico , Síndrome de Cushing/diagnóstico , Neoplasias del Timo/diagnóstico , Síndrome de ACTH Ectópico/complicaciones , Síndrome de ACTH Ectópico/metabolismo , Adenoma Hipofisario Secretor de ACTH/diagnóstico por imagen , Adenoma/diagnóstico por imagen , Hormona Adrenocorticotrópica/sangre , Adulto , Amenorrea/etiología , Carcinoma Neuroendocrino/complicaciones , Carcinoma Neuroendocrino/metabolismo , Síndrome de Cushing/etiología , Síndrome de Cushing/metabolismo , Errores Diagnósticos , Femenino , Humanos , Hidrocortisona/sangre , Hidrocortisona/orina , Debilidad Muscular/etiología , Obesidad Abdominal/etiología , Radiografía Torácica , Estrías de Distensión/etiología , Neoplasias del Timo/complicaciones , Neoplasias del Timo/metabolismo , Tomografía Computarizada por Rayos X , Aumento de PesoRESUMEN
BACKGROUND: Bilateral inferior petrosal sinus sampling (IPSS) with corticotropin-releasing hormone (CRH) is currently the gold standard in the diagnosis of Cushing's disease (CD) and has also been used in tumour lateralization. Our objective was to determine the diagnostic value and lateralization accuracy of IPSS with desmopressin. METHODS: We retrospectively analysed 91 patients with Cushing's syndrome who had either negative findings on pituitary dynamic enhanced magnetic resonance imaging (MRI) or nonsuppressed high-dose dexamethasone suppression tests (HDDST). Thin-slice thoracoabdominal computed tomography (CT) and octreotide receptor imaging of whole body were also negative to rule out ectopic adrenocorticotropin hormone (ACTH) syndrome. All patients went through IPSS with desmopressin. Afterwards, transsphenoidal pituitary surgery, light microscope pathology and immunohistological staining for ACTH were performed in all patients. RESULTS: Diagnosis of CD. Among the 91 patients included, 90 were confirmed with CD, of whom 89 had positive IPSS findings, therefore the sensitivity was 98.9%. The one patient who was negative for CD also had negative IPSS findings, therefore the specificity was 100%. Tumour lateralization. Among the 51 patients who were ultimately diagnosed with CD and whose lateralization by IPSS and surgery was either left or right, 37 had IPSS lateralization in concordance with surgery, therefore the concordance rate was 72.5%. Patients in the concordant group had a higher frequency of right lateralization by surgery. CONCLUSIONS: IPSS with desmopressin is a sensitive approach in the diagnosis of CD and has moderate accuracy in tumour lateralization, making it an alternative choice to IPSS with CRH.
Asunto(s)
Desamino Arginina Vasopresina/metabolismo , Muestreo de Seno Petroso/métodos , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/diagnóstico , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/metabolismo , Síndrome de ACTH Ectópico/diagnóstico , Síndrome de ACTH Ectópico/metabolismo , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Programas InformáticosAsunto(s)
Síndrome de ACTH Ectópico/genética , Endopeptidasas/genética , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Neoplasias/genética , Ubiquitina Tiolesterasa/genética , Síndrome de ACTH Ectópico/metabolismo , Hormona Adrenocorticotrópica/sangre , Hormona Adrenocorticotrópica/metabolismo , Línea Celular Tumoral , Síndrome de Cushing/genética , Síndrome de Cushing/metabolismo , Endopeptidasas/metabolismo , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Receptores ErbB/metabolismo , Femenino , Humanos , Masculino , Neoplasias/metabolismo , Ubiquitina Tiolesterasa/metabolismoRESUMEN
OBJECTIVE: Ectopic adrenocorticotropic hormone (ACTH) secretion is a less common cause of Cushing syndrome and is seen in 5 to 10% of cases with endogenous hypercortisolemia. We hereby describe our experience of patients with ectopic ACTH syndrome, who have been managed over the past 10 years at a tertiary care center in Southern India. METHODS: The inpatient and outpatient records of patients from 2006 to 2015 were retrospectively reviewed. The clinical features, clinical history, biochemical values, imaging features, including radiologic findings and positron emission tomography scans, management, details of follow-up, and outcomes, were documented. We compared the biochemical findings in these patients with 20 consecutive patients with Cushing disease (Cushing syndrome of pituitary origin). RESULTS: A total of 21 patients were studied. The median age at presentation was 34 years (range, 19 to 55 years). Seven patients had thymic carcinoid, 7 had bronchial carcinoid, 3 had lung malignancies, 2 had medullary carcinoma thyroid, 1 patient had a pancreatic neuroendocrine tumor, and 1 patient had an occult source of ACTH. The most common clinical features at presentation were muscle weakness (95%), hyperpigmentation (90%), facial puffiness (76%), easy bruising (61%), edema (57%), and striae (52%). Extensive acne was seen in a large number of patients (43%). Only 3 patients (14%) had central obesity. The median 8 am cortisol was 55.5 µg/dL (range, 3.8 to 131 µg/dL), median 8 am ACTH was 207 pg/mL (range, 31.1 to 703 pg/mL), and the median 24-hour urinary free cortisol was 2,484 µg (range, 248 to 25,438 µg). Basal cortisol and ACTH, as well as midnight cortisol and ACTH level, were markedly higher in patients with ectopic Cushing syndrome as compared to patients with Cushing disease. Twelve of 21 patients had developed life-threatening infections by follow-up. Nine patients had undergone surgical intervention to address the primary tumor. However, only 1 patient exhibited a complete cure on follow-up. CONCLUSION: In our series, ectopic Cushing syndrome was most commonly seen in association with intrathoracic tumors such as bronchial or thymic carcinoid. Hyperpigmentation and proximal myopathy were frequent, while central obesity was uncommon. Early and rapid control of hypercortisolemia was important in order to prevent life-threatening infections and metabolic complications. ABBREVIATIONS: ACTH = adrenocorticotropic hormone CT = computed tomography DOTATATE = 68Ga-DOTA-Tyr3-octreotate ECS = ectopic Cushing syndrome FDG = fluorodeoxyglucose MTC = medullary thyroid cancer NET = neuroendocrine tumor PET = positron emission tomography.
Asunto(s)
Síndrome de ACTH Ectópico/fisiopatología , Síndrome de Cushing/fisiopatología , Neoplasias/metabolismo , Síndrome de ACTH Ectópico/complicaciones , Síndrome de ACTH Ectópico/diagnóstico por imagen , Síndrome de ACTH Ectópico/metabolismo , Acné Vulgar/etiología , Adulto , Neoplasias de los Bronquios/diagnóstico por imagen , Neoplasias de los Bronquios/metabolismo , Tumor Carcinoide/diagnóstico por imagen , Tumor Carcinoide/metabolismo , Carcinoma Neuroendocrino/diagnóstico por imagen , Carcinoma Neuroendocrino/metabolismo , Síndrome de Cushing/etiología , Síndrome de Cushing/metabolismo , Edema/epidemiología , Femenino , Humanos , Hidrocortisona/metabolismo , Hiperpigmentación/etiología , India , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Debilidad Muscular/etiología , Neoplasias/diagnóstico por imagen , Tumores Neuroendocrinos/diagnóstico por imagen , Tumores Neuroendocrinos/metabolismo , Obesidad Abdominal/etiología , Compuestos Organometálicos , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/metabolismo , Tomografía de Emisión de Positrones , Radiofármacos , Estudios Retrospectivos , Centros de Atención Terciaria , Neoplasias del Timo/diagnóstico por imagen , Neoplasias del Timo/metabolismo , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/metabolismo , Adulto JovenRESUMEN
The remarkable conservation of the primary structures and anatomical location of dogfish α-melanocyte-stimulating hormone (MSH), corticotrophin-like intermediate lobe peptide (CLIP) and adrenocorticotrophic hormone (ACTH) compared with mammals reinforced the tissue-specific processing hypothesis of ACTH peptides in the pituitary gland. The cloning of dogfish pro-opiomelanocortin (POMC) led to the identification of δ-MSH and simultaneously revealed the high conservation of the γ-MSH sequence during evolution. These studies have also shown that ß-MSH is much less conserved during evolution and in some species is not even processed from ß-LPH. Human pro-γ-MSH potentiates the corticosteroidogenic activity of ACTH and peptides generated from its N-terminal, in particular big-γ-MSH, appear to have adrenal mitogenic activity. Human big-γ-MSH (from the zona intermedia) may also cause the adrenache. The review finishes with a cautionary note with regard to the misdiagnosis of the ectopic ACTH syndrome in which partial processing of ACTH can result in large concentrations of α-MSH and CLIP, which can interfere in the performance of two-site immunoassays, and the problem of the correct disulphide bridge arrangement in synthetic N-POMC peptides is also discussed.
Asunto(s)
Hormona Adrenocorticotrópica/aislamiento & purificación , Hormonas Estimuladoras de los Melanocitos/aislamiento & purificación , Proopiomelanocortina/aislamiento & purificación , Síndrome de ACTH Ectópico/sangre , Síndrome de ACTH Ectópico/metabolismo , Glándulas Suprarrenales/metabolismo , Hormona Adrenocorticotrópica/sangre , Hormona Adrenocorticotrópica/química , Hormona Adrenocorticotrópica/genética , Animales , Péptido de la Porción Intermedia de la Adenohipófisis Similar a la Corticotropina/química , Péptido de la Porción Intermedia de la Adenohipófisis Similar a la Corticotropina/genética , Péptido de la Porción Intermedia de la Adenohipófisis Similar a la Corticotropina/aislamiento & purificación , Historia del Siglo XX , Humanos , Hormonas Estimuladoras de los Melanocitos/sangre , Hormonas Estimuladoras de los Melanocitos/química , Hormonas Estimuladoras de los Melanocitos/genética , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/sangre , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/metabolismo , Hipófisis/metabolismo , Proopiomelanocortina/química , Proopiomelanocortina/genética , Proopiomelanocortina/historia , Isoformas de Proteínas , alfa-MSH/química , alfa-MSH/genética , alfa-MSH/aislamiento & purificación , betaendorfina/química , betaendorfina/genética , betaendorfina/aislamiento & purificaciónRESUMEN
Ectopic adrenocorticotropic hormone secretion is responsible for 12% to 17% of all cases of the Cushing syndrome. One of the most commonly described causes of ectopic adrenocorticotropic hormone secretion is small cell carcinoma of the lung. A rare cause includes a functioning neuroendocrine tumor traditionally known as carcinoids that account for 5% of all mediastinal tumors. To our knowledge, all reported cases of mediastinal carcinoids are thymic in origin and only a minority of those is functional. We present a male patient with hypertension, obstructive sleep apnea, and acid-base disorder, in whom further investigation revealed an anterior mediastinal mass and Cushing syndrome.
Asunto(s)
Síndrome de ACTH Ectópico/complicaciones , Hipertensión/etiología , Hipopotasemia/etiología , Tumores Neuroendocrinos/complicaciones , Apnea Obstructiva del Sueño/etiología , Neoplasias del Timo/complicaciones , Síndrome de ACTH Ectópico/diagnóstico , Síndrome de ACTH Ectópico/metabolismo , Dolor en el Pecho/etiología , Síndrome de Cushing/etiología , Síndrome de Cushing/metabolismo , Humanos , Hidrocortisona/metabolismo , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/diagnóstico por imagen , Tumores Neuroendocrinos/metabolismo , Radiografía , Neoplasias del Timo/diagnóstico por imagen , Neoplasias del Timo/metabolismoRESUMEN
We describe a rare case of ectopic Cushing's syndrome that recurred 6 years after resection of a thymic neuroendocrine carcinoma. We discuss reasons for the differing clinical presentations, management, hormone profiles, as well as immunopathology. A 41-year-old male developed acute-onset Cushing's syndrome. Clinical presentation and laboratory results were compatible with ectopic adrenocorticotropin hormone (ACTH) production. Computerized tomography (CT) showed a 3.6 cm thymic tumor which was successfully resected. Plasma ACTH (P-ACTH) normalized the first postoperative day. Histopathology demonstrated a well-differentiated neuroendocrine carcinoma with diffuse positivity for ACTH and focal corticotropin-releasing hormone (CRH) reactivity in a few scattered cells. The patient was in remission for 6 years. He then again presented with acute-onset Cushing's syndrome. Fluorine-labeled dihydroxyphenylalanine ((18)F-DOPA) PET/CT showed local uptake in the mediastinum and he underwent repeat resection. However, P-ACTH remained increased (613 ng/l) and 24-h urinary cortisol was 36,720 nmol, suggesting incomplete tumor removal or metastatic spread. Metyrapone treatment was initiated but then withdrawn because the patient spontaneously recovered and cortisol metabolism gradually normalized within 3 weeks. Histopathology demonstrated a recurrent neuroendocrine carcinoma with the same features as the previous lesion but this time CRH was strongly positive in more numerous cells. Normalization of P-ACTH after primary surgery was compatible with ectopic ACTH production. However, the delayed fall in P-ACTH and serum cortisol is compatible with ectopic CRH production and stimulation of pituitary ACTH secretion, which gradually resolved. Although ectopic CRH production is very rare, the unusual dynamics illustrated here should raise the possibility of CRH production by a neuroendocrine tumor.