Recommendations of the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism for the diagnosis of Cushing's disease in Brazil

ABSTRACT Although it is a rare condition, the accurate diagnosis and treatment of Cushing’s disease is important due to its higher morbidity and mortality compared to the general population, which is attributed to cardiovascular diseases, diabetes mellitus and infections. Screening for hypercortisolism is recommended for patients who present multiple and progressive clinical signs and symptoms, especially those who are considered to be more specific to Cushing’s syndrome, abnormal findings relative to age (e.g., spinal osteoporosis and high blood pressure in young patients), weight gain associated with reduced growth rate in the pediatric population and for those with adrenal incidentalomas. Routine screening is not recommended for other groups of patients, such as those with obesity or diabetes mellitus. Magnetic resonance imaging (MRI) of the pituitary, the corticotropin-releasing hormone (CRH) test and the high-dose dexamethasone suppression test are the main tests for the differential diagnosis of ACTH-dependent Cushing’s syndrome. Bilateral and simultaneous petrosal sinus sampling is the gold standard method and is performed when the triad of initial tests is inconclusive, doubtful or conflicting. The aim of this article is to provide information on the early detection and establishment of a proper diagnosis of Cushing’s disease, recommending follow-up of these patients at experienced referral centers. Arch Endocrinol Metab. 2016;60(3):267-86.

Paresia del III par craneal como manifestación de un corticotropinoma silente / Third nerve palsy as an expression of a corticotroph adenoma

Silent corticotroph adenomas (SCA) are pituitary adenomas inmunoreactive to ACTH without hormonal overproduction and they form the 3 percent of the pituitary adenomas. Unlike the ademonas that cause the Cushing’s disease, frequently the SCA are aggressive macroademonas and their clinical expressions are the compromise of nearby structures with or without pituitary apoplexy. Frequently, the treatment chosen is a surgical procedure, albeit the total resection difficulties. The SCA are not diagnosed until an anatomopathological and immunohistochemical study is carried out. In this document, a case study of a woman diagnosed with a clinically silent macrocorticotroph adenomadiscovered by a third nerve palsy is explained.

Adenoma corticotrópos silente de la glándula pituitaria / Silent corticotroph adenomas of the pituitary gland

Objetivos: En el presente trabajo se revisará nuestra serie de casos de Adenomas Corticotrópos silentes y revisar la literatura acerca de esta patología fascinante. Material y Método: Se revisaron las historias clínicas de 5 pacientes del Hospital Universitario Fundación Santa Fé de Bogotá en el periodo de enero de 1990 a enero de 2008, que se le realizó tratamiento para una masa sellar y se le realizó diagnóstico patológico de Adenoma Corticotrópos Silente. Discusión: Los adenomas de hipófisis corresponden entre el 17 por ciento de los tumores intracraneales. El 60 por ciento de estas lesiones se asocian a hipersecreción hormonal. Los adenomas corticotropos silentes son tumores hipofisarios que histológicamente muestran diferenciación corticotrópica con algún grado de secreción de ACTH pero sin la evidencia clínica de síndrome de Cushing. Conclusión: Aunque estos tumores sean clínicamente significativos y su histopatología fascinante, hay poca literatura y estudios clínicos con enfoque especial sobre estas lesiones. Estos tumores son muy importantes tenerlos en cuenta en la patología selar ya que su tratamiento requiere mayor dedicación y seguimiento a estos pacientes.

Objectives: In the present paper we want to review our series of silent corticotrofic adenomas and review the literature concerning this fascinating pathology. Material and Methods: we review the clinical history of 5 patients treated and diagnosed with Silent corticotrofic adenomas in University Hospital Fundacion Santa Fe de Bogota in the period of January 1990 till January 2008. Discussion: Pituitary adenomas count for 10 to 15 percent of intracranial tumors. In 60 percent of the cases there is a hormonal hypersecretory syndrome associated with these mass. Silent Corticotophic adenomas are pituitary tumors which histologically show a corticotrophic differentiation with secretion of ACTH but do not present with clinical evidence of Cushing disease. Although silent corticotophic adenomas are clinically significant and histologically fascinating there are only few clinical studies and medical literature with regard to these tumors. Conclusion: Although silent corticotophic adenomas are clinically significant and histologically fascinating there are only few clinical studies and medical literature with regard to these tumors. It is very important to take in regard this tumor in the pathology of the selar region since these patients demand a major dedication and a strict follow up.

Imaging in Cushing's syndrome: [review]

Once the diagnosis of Cushing's syndrome (CS) has been established, the main step is to differentiate between ACTH dependent and independent disease. In adults, 80 percent of CS is due to ACTH-dependent causes and 20 percent due to adrenal causes. ACTH-secreting neoplasms cause ACTH-dependent CS. These are usually anterior pituitary microadenomas, which result in the classic Cushing's disease. Non-pituitary ectopic sources of ACTH, such as a small-cell lung carcinoma or carcinoid tumours, are the source of the remainder of ACTH-dependent disease. In the majority of patients presenting with clinical and biochemical evidence of CS, modern non-invasive imaging can accurately and efficiently provide the cause and the nature of the underlying pathology. Imaging is essential for determining the source of ACTH in ectopic ACTH production, locating the pituitary tumours and distinguishing adrenal adenomas, carcinomas and hyperplasias. In our chapter we review the adrenal appearances in ACTH-dependent and ACTH-independent CS. We also include a discussion on the use of MRI and CT for the detection and management of pituitary ACTH secreting adenomas. CT of the chest, abdomen and pelvis with intravenous injection of contrast medium is the most sensitive imaging modality for the identification of the ectopic ACTH source and detecting adrenal pathology. MRI is used for characterising adrenal adenomas, problem solving in difficult cases and for detecting ACTH-secreting pituitary adenomas.

Uma vez estabelecido o diagnóstico da síndrome de Cushing (SC), o passo principal é diferenciar entre a doença ACTH-dependente e a independente. Em adultos, 80 por cento da SC é devida a causas ACTH-dependentes e 20 por cento a causas adrenais. Neoplasias secretoras de ACTH causam a SC ACTH-dependente: usualmente são microadenomas da hipófise anterior que resultam na clássica doença de Cushing. Fontes ectópicas (não hipofisárias) de ACTH, como o carcinoma pulmonar de células pequenas e tumores carcinóides, são a origem do restante da doença ACTH-dependente. Na maioria dos pacientes que se apresentam com evidências clínicas e bioquímicas da SC, técnicas modernas de imagem não invasivas podem apontar acurada e eficientemente a causa e a natureza da patologia subjacente. A imagem é essencial para a determinação da fonte de ACTH na produção ectópica desse hormônio, na localização de tumores hipofisários e na distinção entre adenomas, carcinomas e hiperplasias adrenais. Nesse artigo revisaremos a imagem adrenal na SC ACTH-dependente e independente. Incluiremos, também, uma discussão sobre o uso da RM e da TC na detecção e manejo dos adenomas hipofisários secretores de ACTH. TC de tórax, abdome e pelve, com a injeção intravenosa de meio de contraste, é a modalidade de imagem mais sensível para a identificação da fonte ectópica de ACTH e na detecção da patologia adrenal. A RM é empregada para a caracterização de adenomas adrenais, para a solução de problemas em casos difíceis e para a detecção de adenomas hipofisários secretores de ACTH.

The role of bilateral inferior petrosal sinus sampling in the diagnosis of Cushing's syndrome

Adrenocorticotropin hormone (ACTH)-dependent Cushing's syndrome is most often due to a pituitary corticotroph adenoma, with ectopic ACTH-secreting tumors representing approximately 15 percent of cases. Biochemical and radiological techniques have been established to help distinguish between these two entities, and thus aid in the localization of the neoplastic lesion for surgical resection. The test that offers the highest sensitivity and specificity is bilateral inferior petrosal sinus sampling (BIPSS). BIPSS is an interventional radiology procedure in which ACTH levels obtained from venous drainage very near the pituitary gland are compared to peripheral blood levels before and after corticotropin hormone (CRH) stimulation. A gradient between these two locations indicates pituitary Cushing's, whereas the absence of a gradient suggests ectopic Cushing's. Accurate BIPSS results require hypercortisolemia to suppress normal corticotroph ACTH production and hypercortisolemia at the time of the BIPSS to assure excessive ACTH secretion. In some cases, intrapituitary gradients from side-to-side can be helpful to localize small corticotroph adenomas within the sella. BIPSS has rare complications and is considered safe when performed at centers with experience in this specialized technique.

A síndrome de Cushing (SC) ACTH-dependente é mais freqüentemente devida a um adenoma corticotrófico da hipófise, com os tumores ectópicos secretores de ACTH representando aproximadamente 15 por cento dos casos. Técnicas bioquímicas e radiológicas foram estabelecidas para permitir a distinção entre essas duas entidades e, assim, auxiliar na localização da lesão neoplásica para ressecção cirúrgica. O teste que oferece a mais alta sensibilidade e especificidade é a coleta bilateral de amostras de sangue do seio petroso inferior (BIPSS). BIPSS é um procedimento de intervenção radiológica no qual os níveis de ACTH obtidos da drenagem venosa bem próxima da hipófise são comparados com os níveis sanguíneos periféricos antes e após estímulo com corticorrelina (CRH). Um gradiente entre essas duas localizações indica SC hipofisário, enquanto a ausência de gradiente sugere SC ectópica. Resultados acurados na BIPSS requerem a presença de hipercortisolemia e que ela suprima normalmente a produção de ACTH pelo corticotrofos por ocasião da BIPSS para garantir a secreção excessiva de ACTH. Em alguns casos, os gradientes intra-hipofisários de um lado para outro podem ser úteis na localização de pequenos adenomas corticotróficos no interior da sela. A BIPSS raramente apresenta complicações, sendo considerada segura quando realizada em centros com experiência nessa técnica especializada.