The 4Ds of ectopic ACTH syndrome: diagnostic dilemmas of a difficult disease

SUMMARY Cushing's syndrome (CS) is an uncommon condition that leads to high morbidity and mortality. The majority of endogenous CS is caused by excessive ACTH secretion, mainly due to a pituitary tumor - the so-called Cushing's disease (CD) - followed by ectopic ACTH syndrome (EAS), an extra-pituitary tumor that produces ACTH; adrenal causes of CS are even rarer. Several methods are used to differentiate the two main etiologies: specific laboratory tests and imaging procedures, and bilateral inferior petrosal sinus sampling (BIPSS) for ACTH determination; however, identification of the source of ACTH overproduction is often a challenge. We report the case of a 28-year-old woman with clinical and laboratory findings consistent with ACTH-dependent CS. All tests were mostly definite, but several confounding factors provoked an extended delay in identifying the origin of ACTH secretion, prompting a worsening of her clinical condition, with difficulty controlling hyperglycemia, hypokalemia, and hypertension. During this period, clinical treatment was decisive, and measurement of morning salivary cortisol was a differential for monitoring cortisol levels. This report shows that clinical reasoning, experience and use of recent methods of nuclear medicine were decisive for the elucidation of the case.

A rare case of ectopic ACTH syndrome originating from malignant renal paraganglioma

SUMMARY Ectopic adrenocorticotropic hormone (ACTH) syndrome is characterized by hypercortisolism due to the hypersecretion of a non-pituitary ACTH-secreting tumor leading to Cushing's syndrome. Only a few cases have been reported previously as causing ectopic ACTH related to paraganglioma. Herein, we present a case of Cushing's syndrome, in who was proved to be attributable to an ACTH-secreting renal malignant paraganglioma. A 40-year-old woman presented with a five-month history of newly diagnosed hypertension and diabetes, weakness, hyperpigmentation, oligomenorrhea, hirsutism, and acneiform lesions. She showed cushingoid features, including moon face, facial hirsutism, facial and truncal acne, hyperpigmentation, and severe muscle weakness of the limbs. She did not have other findings such as striae, supraclavicular fat accumulation, and buffalo hump. Laboratory examination showed the presence of hypopotasemia, hyperglycemia, hyperthyroidism, and leukocytosis. The serum levels of ACTH, cortisol, and urine-free cortisol were markedly elevated. Results of an overnight 2-mg dexamethasone suppression test included a basal serum cortisol of 61.1 mcg/dL (normal range: 4.6-22.8 mcg/dL) and a cortisol value of 46.1 mcg/dL after dexamethasone administration. There was no suppression found after 2-day 8-mg dexamethasone administration. Magnetic resonance imaging (MRI) of the pituitary gland indicated two microadenomas. An abdominal MRI scan revealed horseshoe kidney, bilateral adrenal hyperplasia, and masses with dimensions of 35 x 31 mm in the left kidney. Inferior petrosal sinus sampling showed no evidence of a central-to-peripheral gradient of ACTH. A positron emission tomography/computed tomography scan showed intense increased activity in the lower pole of the left kidney. Left adrenalectomy and left partial nephrectomy were performed. The resected tumor was diagnosed as the ACTH-secreting paraganglioma in the pathological examination, which was confirmed by immunohistochemical studies with chromogranin A, synaptophysin, and ACTH. Only a few cases of paragangliomas as a cause of ectopic ACTH syndrome have been reported. To our knowledge, this is the first case of renal paraganglioma resulting in Cushing's syndrome due to ectopic ACTH hypersecretion.

Secreción ectópica de ACTH en un paciente con antecedentes de enfermedad de Cushing / ACTH's ectopic secretion in a patient with precedents of Cushing's disease

Hombre de 54 años con antecedentes de enfermedad de Cushing 32 años antes de la consulta. Ingresó por edemas asociados a astenia y adinamia. En el laboratorio se constató hipopotasemia y alcalosis metabólica. Se realizó diagnóstico humoral de síndrome de Cushing secundario a secreción ectópica de hormona adrenocorticotropa (ACTH). En la tomografía de tórax se halló un tumor de 3 × 3 cm en el mediastino anterior. La anatomía patológica de la pieza quirúrgica fue compatible con un carcinoide tímico. Este paciente sufrió en dos oportunidades un síndrome de Cushing, la primera por enfermedad (adenoma hipofisiario) y la segunda vez por secreción ectópica de ACTH (SEA) una asociación no descripta, en nuestro conocimiento, en la literatura médica.

A 54-year-old man, with a history of Cushing’s disease diagnosed 32 years earlier, presented with edema, asthenia and general malaise. Abnormal laboratory studies depicted hypokalemia and metabolic alkalosis. A CT scan of the chest revealed a 3 × 3 cm tumor in the anterior mediastinum. The pathology was consistent with a thymic carcinoid. These findings led to a diagnosis of biochemical Cushing’s syndrome secondary to ectopic secretion of ACTH. Thus, this patient suffered twice of Cushing’s syndrome. The first instance was the consequence of an ACTH - secreting pituitary adenoma and the second of an ectopic secretion of ACTH. To the best of our knowledge this is the first such case reported in the medical literature.

Síndrome de Cushing por ACTH ectópica: revisión a propósito de dos casos clínicos / Cushing syndrome caused by ectopic ACTH secretion: report of two cases

Twelve percent of Cushing syndromes (CS) are caused by ectopic ACTH secretion. We report two cases of the condition. A 57 years old woman with an ectopic CS caused by a bronchial carcinoid tumor. After the tumor excision, the patient had a favorable evolution. A 63 years old woman consulting for cough, dyspnea and weight loss causes by a small cell lung cancer. The patient presented hyperglycemia, hypokalemia and metabolic alcalosis. The laboratory showed a severe hypercortisolism with elevated ACTH levels. The metabolic condition did not subside after the first course of chemotherapy and the patient died due to an infectious complication...

Ectopic ACTH syndrome

Ectopic adrenocorticotropic secretion (EAS) is responsible for 12-17 percent of cases of Cushing's syndrome (CS) and covers a range of tumours, from undetectable benign lesions to widespread metastases. The syndrome is often associated with severe hypercortisolaemia, which aggravates the underlying condition. EAS requires a complete workup that includes the establishment of endogenous CS, diagnosis of adrenocorticotropic hormone (ACTH) dependency, localization of the source of ACTH secretion and rapid biochemical control of hypercortisolaemia. Dynamic endocrine tests should include inferior petrosal sinus sampling with CRH stimulation. Localization studies depend on the availability of reliable high-resolution cross-sectional imaging. This systematic review of the largest published series of patients with EAS (over 380 patients) reveals the common trends in the prevalence and management of this syndrome. The concept of 'occult' EAS has been revisited and the terms 'overt' and 'covert' EAS introduced. In addition to small cell lung carcinoma, the most common causes of ectopic EAS are bronchial carcinoids, thymic tumours, islet cell tumour of the pancreas, medullary thyroid carcinomas, and phaeochromocytomas. Their prevalence and the best localization modalities are presented. Medical and surgical management is discussed on the basis of the extensive experience of major referral centres.

A secreção ectópica de ACTH (SEA) é responsável por 12-17 por cento dos casos de síndrome de Cushing (SC), cobrindo uma variedade de tumores, desde lesões benignas indetectáveis a metástases disseminadas. A SEA está freqüentemente associada com hipercortisolemia grave, que agrava a condição de base e requer uma avaliação completa, que inclui a confirmação da SC endógena, o diagnóstico da dependência ao ACTH, a localização da fonte da secreção de ACTH e o controle bioquímico rápido da hipercortisolemia. Testes endócrinos dinâmicos devem incluir a coleta de amostras do seio petroso inferior com estímulo pelo CRH. O estudo da localização da fonte depende da disponibilidade de procedimentos de imagem de alta-resolução confiáveis. A revisão sistemática das maiores séries publicadas de pacientes com SEA (mais de 380 pacientes) revela tendências comuns na prevalência e manejo dessa síndrome. O conceito de SEA "oculta" está sendo revisado e os termos SEA "manifesta" e "latente" são introduzidos. Além do carcinoma pulmonar de pequenas células, as causas mais comuns de SEA são os carcinóides brônquicos, tumores tímicos, tumor de ilhotas pancreáticas, carcinoma medular de tiróide e feocromocitoma; sua prevalência e as melhores modalidades para localização são apresentadas. O manejo clínico e cirúrgico é discutido com base na vasta experiência dos principais centros de referência.

Síndrome de cushing endógena: características clínico-laboratoriais em 73 casos / Endogenous cushings syndrome: clinical and laboratorial features in 73 cases

Avaliamos as características clínico-laboratoriais de 73 pacientes com síndrome de Cushing (SC) endógena, assim distribuídos: 46 (63 por cento) com doença de Cushing (DC), 21 (28,7 por cento) com tumores adrenais (TA) e 6 (8,2 por cento) com a síndrome do ACTH ectópico (SAE). A freqüência de manifestações clássicas do hipercortisolismo foi similar, independentemente da etiologia da SC. Em 100 por cento dos casos de SC, observaram-se níveis do cortisol sérico (CS) > 1,8 µg/dL após supressão com doses baixas de dexametasona (DMS), além de elevação do cortisol à meia-noite (sérico ou salivar). Contudo, o cortisol livre urinário foi normal em 11,5 por cento dos pacientes. Os níveis de ACTH mostraram-se suprimidos nos pacientes com TA, normais ou elevados na DC e sempre elevados na SAE. No teste de supressão noturna com 8 mg de DMS, supressão do CS > 50 por cento foi observada em 78,2 por cento dos casos de DC e 33,3 por cento dos casos de SAE, enquanto uma supressão > 80 por cento foi exclusiva da DC. Após estímulo com CRH ou DDAVP, um incremento do ACTH > 35 por cento aconteceu em 81 por cento dos indivíduos com DC e em 16,6 por cento daqueles com SAE, ao passo que um incremento do ACTH > 50 por cento restringiu-se à DC. A combinação de incremento do ACTH > 35 e supressão do CS > 50 por cento foi também exclusiva da DC. A ressonância magnética visualizou 100 por cento dos macroadenomas e 59,4 por cento dos microadenomas hipofisários nos casos de DC. Em 10 pacientes submetidos ao cateterismo bilateral do seio petroso inferior, um gradiente centro-periferia de ACTH > 3 pós-CRH ou DDAVP teve sensibilidade de 90 por cento e especificidade de 100 por cento para a doença de Cushing.

We studied clinical and laboratorial features of 73 patients with endogenous Cushings syndrome, subdivided as follows: 46 (63 percent) with Cushings disease (CD), 21 (28.7 percent) with an adrenal tumor and 6 (8.2 percent) with ectopic ACTH secretion (EAS). The rate of typical manifestations of hypercortisolism was similar regardless its etiology. In 100 percent of cases of Cushings syndrome we observed serum cortisol levels greater than 1.8 µg/dL in low-dose dexamethasone (DMS) suppression tests, as well as elevation of serum or salivary midnight cortisol. However, urinary free cortisol was normal in 11.5 percent of patients. ACTH levels were suppressed in patients with adrenal tumors, normal or high in CD and always high in EAS. In the 8-mg overnight DMS suppression test, serum cortisol suppression > 50 percent was observed in 78.2 percent of cases of CD and in 33.3 percent of subjects with EAS, while an 80 percent suppression was only seen in CD. After stimulation with CRH or DDAVP an ACTH increase > 35 percent occurred in 81 percent of individuals with CD and 16.6 percent of those with EAS, while an ACTH increase > 50 achieved 100 percent specificity. Moreover, the combination of serum cortisol suppression > 50 percent and an ACTH increase > 35 percent in both tests only occurred in Cushings disease. Pituitary magnetic resonance imaging identified 100 percent of macroadenomas and 59.4 percent of microadenomas in patients with CD. Among 10 patients that underwent bilateral inferior petrosal sinus sampling, a central-to-peripheral ACTH gradient > 3 after CRH or DDAVP had 90 percent sensitivity and 100 percent specificity for Cushings disease.

The ectopic ACTH syndrome and superior vena cava obstruction due to a malignant carcinoid tumour of the thymus

We report the case of a 28-year-old African Caribbean woman with Cushing's syndrome and superior vena cava obstruction secondary to an ACTH-secreting carcinoid tumour of the thymus. The case highlights the problems which may be encountered in performing the 2-day high dose dexamethasone suppression test but clinicians are reminded that this test or any other dynamic test is absolutely essential for elucidating the cause of ACTH-dependent Cushing's Syndrome.

Ectopic ACTH syndrome due to bronchial carcinoid tumour--a case report.

A patient is reported who had Cushing's syndrome and carcinoid tumour of the bronchus. The case illustrates the difficulty in preoperative localization of the ectopic ACTH source and the surgical management of such patients.