Limited significance of repeated long-term radiological and hormonal examination in nonfunctioning adrenal incidentalomas

ABSTRACT Purpose: The purposes of the present study were to evaluate growth rate of nonfunctioning adrenal incidentalomas (AIs) and their development to hormonal hypersecretion on follow-up. Materials and methods: A retrospective study was conducted from the electronic medical records. A total of 314 patients were diagnosed with adrenal tumors between 2000 and 2016. After excluding patients who had overt adrenal endocrine disorders or whose adrenal tumors were clinically diagnosed as metastatic malignancies, we investigated 108 patients with nonfunctioning AIs including characteristics, the treatment, the way of follow-up and pathology. Results: Fifteen patients received immediate adrenalectomy because of the initial tumor size or patient's preference. Pathological examination revealed malignancy in 2 patients. In the remaining 93 patients, radiological examinations were performed periodically. Tumor enlargement of ≥ 1.0cm was observed in 8.6% of the patients who were followed up as nonfunctioning AIs with a median follow-up period of 61.5 months (range: 4-192). Eleven patients underwent adrenalectomy. On the pathological examinations, all of the tumors, which showed a size increase, were diagnosed as benign tumors. Regarding the followed up patients without adrenalectomy, only 2.4% of the patients had tumor enlargement during the prolonged follow-up. Furthermore, none of the patients developed hormonal hypersecretion or clinical signs such as obesity, glucose intolerance or poorly controlled hypertension. Conclusions: Tumor enlargement of AIs did not correlate with malignancy. The value of repeat radiological and hormonal examinations may be limited in the long-term follow-up of patients whose AIs are not enlarged.

Feocromocitoma quístico gigante: reporte de un caso / Pheochromocytoma giant cystic: a case report

El feocromocitoma quístico gigante es tumor adrenal raro en el que predomina el curso asintomático; por lo que muchos de los casos no son diagnosticados hasta el momento de la cirugía. La simple movilización del tumor se asocia con el paso a la sangre de grandes cantidades de catecolaminas y a una elevada morbimortalidad.; por esta razón la cirugía per se y su manejo perioperatorio constituyen un enorme desafío. En este artículo se presenta el caso de un feocromocitoma gigante maligno (35 cm) que ocupaba todo el hemiabdomen derecho. Aun con el diagnóstico preoperatorio de feocromocitoma, el bloqueo farmacológico preoperatorio y las medidas intraoperatorias, el paciente falleció poco antes de que finalizara la cirugía.

The giant cystic pheochromocytoma is a rare adrenal tumor in the predominantly asymptomatic course; so many cases are not diagnosed until the time of surgery. The simple mobilization of the tumor is associated with the passage to the blood of large amounts of catecholamines and high morbidity and mortality. So the surgery itself and perioperative management are a huge challenge. This article describes the case of a malignant giant pheochromocytoma (35 cm) which occupied the entire right abdomen. Even with the preoperative diagnosis of pheochromocytoma, pharmacological blockade preoperative and intraoperative measures, the patient died shortly before the end of surgery.

Diagnóstico, tratamento e seguimento do carcinoma medular de tireoide: recomendações do Departamento de Tireoide da Sociedade Brasileira de Endocrinologia e Metabologia / Diagnosis, treatment, and follow-up of medullary thyroid carcinoma: recommendations by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism

Introdução O carcinoma medular de tireoide (CMT) origina-se das células parafoliculares da tireoide e corresponde a 3-4% das neoplasias malignas da glândula. Aproximadamente 25% dos casos de CMT são hereditários e decorrentes de mutações ativadoras no proto-oncogene RET (REarranged during Transfection). O CMT é uma neoplasia de curso indolente, com taxas de sobrevida dependentes do estádio tumoral ao diagnóstico. Este artigo descreve diretrizes baseadas em evidências clínicas para o diagnóstico, tratamento e seguimento do CMT. Objetivo O presente consenso, elaborado por especialistas brasileiros e patrocinado pelo Departamento de Tireoide da Sociedade Brasileira de Endocrinologia e Metabologia, visa abordar o diagnóstico, tratamento e seguimento dos pacientes com CMT, de acordo com as evidências mais recentes da literatura. Materiais e métodos: Após estruturação das questões clínicas, foi realizada busca das evidências disponíveis na literatura, inicialmente na base de dados do MedLine-PubMed e posteriormente nas bases Embase e SciELO – Lilacs. A força das evidências, avaliada pelo sistema de classificação de Oxford, foi estabelecida a partir do desenho de estudo utilizado, considerando-se a melhor evidência disponível para cada questão. Resultados Foram definidas 11 questões sobre o diagnóstico, 8 sobre o tratamento cirúrgico e 13 questões abordando o seguimento do CMT, totalizando 32 recomendações. Como um todo, o artigo aborda o diagnóstico clínico e molecular, o tratamento cirúrgico inicial, o manejo pós-operatório e as opções terapêuticas para a doença metastática. Conclusões O diagnóstico de CMT deve ser suspeitado na presença de nódulo tireoidiano e história ...

Introduction Medullary thyroid carcinoma (MTC) originates in the thyroid parafollicular cells and represents 3-4% of the malignant neoplasms that affect this gland. Approximately 25% of these cases are hereditary due to activating mutations in the REarranged during Transfection (RET) proto-oncogene. The course of MTC is indolent, and survival rates depend on the tumor stage at diagnosis. The present article describes clinical evidence-based guidelines for the diagnosis, treatment, and follow-up of MTC. Objective The aim of the consensus described herein, which was elaborated by Brazilian experts and sponsored by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism, was to discuss the diagnosis, treatment, and follow-up of individuals with MTC in accordance with the latest evidence reported in the literature. Materials and methods: After clinical questions were elaborated, the available literature was initially surveyed for evidence in the MedLine-PubMed database, followed by the Embase and Scientific Electronic Library Online/Latin American and Caribbean Health Science Literature (SciELO/Lilacs) databases. The strength of evidence was assessed according to the Oxford classification of evidence levels, which is based on study design, and the best evidence available for each question was selected. Results Eleven questions corresponded to MTC diagnosis, 8 corresponded to its surgical treatment, and 13 corresponded to follow-up, for a total of 32 recommendations. The present article discusses the clinical and molecular diagnosis, initial surgical treatment, and postoperative management of MTC, as well as the therapeutic options for metastatic disease. Conclusions 7 .

Risk of catecholamine crisis in patients undergoing resection of unsuspected pheochromocytoma

PURPOSE: To report the risk of catecholamine crisis in patients undergoing resection of unsuspected pheochromocytoma. MATERIALS AND METHODS: Over a four-year period, we retrospectively identified four patients who underwent resection of adrenal pheochromocytoma in whom the diagnosis was unsuspected based on preoperative clinical, biochemical, and imaging evaluation. RESULTS: None of the patients exhibited preoperative clinical features of catecholamine excess. Preoperative biochemical screening in two patients was normal. CT scan performed in all patients demonstrated a nonspecific enhancing adrenal mass. During surgical resection of the adrenal mass, hemodynamic instability was observed in two of four patients, and one of these two patients also suffered a myocardial infarct. CONCLUSION: Both surgeons and radiologists should maintain a high index of suspicion for pheochromocytoma, as the tumor can be asymptomatic, biochemically negative, and have nonspecific imaging features. Resection of such unsuspected pheochromocytomas carries a substantial risk of intraoperative hemodynamic instability.

Glucose-dependent insulinotropic peptide receptor overexpression in adrenocortical hyperplasia in MEN1 syndrome without loss of heterozygosity at the 11q13 locus

BACKGROUND: The molecular mechanisms involved in the genesis of the adrenocortical lesions seen in MEN1 syndrome (ACL-MEN1) remain poorly understood; loss of heterozygosity at 11q13 and somatic mutations of MEN1 are not usually found in these lesions. Thus, additional genes must be involved in MEN1 adrenocortical disorders. Overexpression of the glucose-dependent insulinotropic peptide receptor has been shown to promote adrenocortical tumorigenesis in a mice model and has also been associated with ACTH-independent Cushing syndrome in humans. However, to our knowledge, the status of glucose-dependent insulinotropic peptide receptor expression in adrenocortical lesions in MEN1 has not been previously investigated. OBJECTIVE: To evaluate glucose-dependent insulinotropic peptide receptor expression in adrenocortical hyperplasia associated with MEN1 syndrome. MATERIALS/METHODS: Three adrenocortical tissue samples were obtained from patients with previously known MEN1 germline mutations and in whom the presence of a second molecular event (a new MEN1 somatic mutation or an 11q13 loss of heterozygosity) had been excluded. The expression of the glucose-dependent insulinotropic peptide receptor was quantified by qPCR using the DDCT method, and b-actin was used as an endogenous control. RESULTS: The median of glucose-dependent insulinotropic peptide receptor expression in the adrenocortical lesions associated with MEN1 syndrome was 2.6-fold (range 1.2 to 4.8) higher than the normal adrenal controls (p = 0.02). CONCLUSION: The current study represents the first investigation of glucose-dependent insulinotropic peptide receptor expression in adrenocortical lesions without 11q13 loss of heterozygosity in MEN1 syndrome patients. Although we studied a limited number of cases of MEN1 adrenocortical lesions retrospectively, our preliminary data suggest an involvement of glucose-dependent insulinotropic peptide receptor overexpression in the etiology of adrenocortical hyperplasia. New prospective studies will be able to clarify the exact role of the glucose-dependent insulinotropic peptide receptor in the molecular pathogenesis of MEN1 adrenocortical lesions.

Dopamine-secreting adrenal ganglioneuroma presenting with paroxysmal hypertension attacks

Adrenal ganglioneuromas are rare tumors originating from the neural crest tissue of the sympathetic nervous system. The clinical presentation for most patients is asymptomatic, and most of these tumors are hormone silent. We report a case of dopamine-secreting adrenal ganglioneuroma associated with paroxysmal hypertensive attacks in an adult patient. A 46-year-old woman was admitted to our hospital with a 2-month history of right flank pain, and a 2-year history of paroxysmal hypertensive attacks associated with headaches, palpitations, nervousness, and sweating. Abdominal CT and MRI revealed a solid round tumor approximately 4 cm in diameter on the upper pole of the right kidney. Urinary levels of dopamine and homovanillic acid were slightly elevated, although urinary levels of metanephrine and normetanephrine were suppressed. The urinary levels of epinephrine, norepinephrine, and vanillylmandelic acid were within normal limits. Right adrenalectomy was performed for treatment purposes. Histological diagnosis of the tumor was a ganglioneuroma originating from the adrenal medulla. In conclusion, this is a case of dopamine-secreting adrenal ganglioneuroma associated with paroxysmal hypertensive attacks in an adult patient

Cellular and molecular abnormalities of a macronodular adrenal hyperplasia causing beta-blocker-sensitive Cushing's syndrome

Cushing's syndrome due to ACTH-independent macronodular adrenal hyperplasia (AIMAH) can be associated with abnormal responses of aberrantly expressed adrenocortical receptors. This study aimed to characterize in vitro the pathophysiology of hypercortisolism in a b-blocker-sensitive Cushing's syndrome due to AIMAH. Cortisol secretion profile under aberrant receptors stimulation revealed hyperresponsiveness to salbutamol (beta2-adrenoceptor agonist), cisapride (5-HT4 receptor agonist), and vasopressin in AIMAH cultured cells, but not in normal adrenocortical cells. By RT-PCR, AIMAH tissues revealed beta2-adrenoceptor overexpression rather than ectopical expression. MC2R expression was similar in both AIMAH and normal adrenocortical tissues. Curiously, cortisol levels of AIMAH cells under basal condition were 15-fold higher than those of control cells and were not responsive to ACTH. Analysis of culture medium from AIMAH cells could detect the presence of ACTH, which was immunohistochemically confirmed. Finally, the present study of AIMAH cells has identified: a) cortisol hyperresponsiveness to catecholamines, 5-HT4 and vasopressin in vitro, in agreement with clinical screening tests; b) abnormal expression of beta2-adrenoceptors in some areas of the hyperplastic adrenal tissue; c) autocrine loop of ACTH production. Altogether, the demonstration of aberrant responses to hormonal receptors and autocrine hormone production in the same tissue supports the assumption of multiple molecular alterations in adrenal macronodular hyperplasia.

A síndrome de Cushing secundária à hiperplasia adrenal macronodular independente de ACTH (AIMAH) pode estar associada com respostas anômalas a estímulos sobre receptores hormonais expressos de maneira aberrante no córtex adrenal. O objetivo deste trabalho foi caracterizar a fisiopatologia do hipercortisolismo in vitro na síndrome de Cushing responsiva a beta-bloqueadores decorrente de AIMAH. Em cultura de células, a secreção de cortisol apresentou resposta aumentada ao salbutamol (agonista beta2-adrenérgico), à cisaprida (agonista de receptor 5-HT4) e à vasopressina, na AIMAH mas não no córtex adrenal normal. O estudo de receptores aberrantes por RT-PCR demonstrou que o gene do receptor beta2-adrenérgico estava superexpresso (e não expresso ectopicamente) nos fragmentos da AIMAH quando comparado ao tecido normal. A expressão de MC2R foi semelhante em ambos. Curiosamente, o nível basal de secreção de cortisol pelas células da AIMAH foi 15 vezes superior às células normais, não havendo resposta das células AIMAH ao estímulo com ACTH. A análise do meio de cultura das células AIMAH revelou a presença de ACTH, que foi confirmada por estudo imuno-histoquímico. Em suma, este estudo demonstrou: a) aumento dos níveis de cortisol in vitro em resposta a catecolaminas, 5-HT4 e vasopressina, correspondendo aos resultados dos testes clínicos para pesquisa de receptores aberrantes; b) expressão anormal de receptores beta2-adrenérgicos em algumas áreas de hiperplasia; c) produção autócrina de ACTH. Estes resultados envolvendo ativação de receptores aberrantes e estímulo hormonal autócrino no mesmo tecido favorecem a hipótese da existência de alterações moleculares múltiplas na hiperplasia adrenal macronodular.

Alteraciones químicas y hematológicas en el feocromocitoma / Chemical and hematological changes of pheochromocytoma

Se presentan los resultados de los estudios de laboratorio, llevados a cabo en 37 pacientes con feocromocitoma. Veinte hombres y 17 mujeres, de edad entre 11 y 55 años. La hiperglucemia de ayuno fue de las alteraciones más frecuentemente observadas (59%). En orden decreciente de frecuencia se encontraron elevados la hemoglobina (62%), los leucocitos (53%), el hematocrito (50%), el colesterol (415), la creatinina sérica (24%) y el número de plaquetas (25%). La diferencia con el promedio normal fue significativa en todas las variables analizadas (p<0.001). En general, no se encontró correlación con niveles urinarios o plasmáticos de catecolaminas. La respuesta a la carga de glucosa fue normal en 9 pacientes; 6 tuvieron una curva francamente diabética y 2 sólo mostraron intolerancia a los hidratos de carbono. En esta serie y en algunos informes de la literatura, este tipo de alteraciones ha dado lugar a diagnósticos erróneos, principalmente en casos con presentación clínica atípica o poco frecuente tales como fiebre de origen desconocido, estado de choque y otros. Por lo tanto, el reconocimiento de estas anormalidades como expresión de la presencia de un feocromocitoma es muy importante tanto desde el punto de vista diagnóstico como terapéutico

Abnormal catecholamine metabolism in pheochromocytoma

En este trabajo se analizan los niveles y características de las enzimas involucradas en la biosíntesis y degradación de las catecolaminas (CA) en el feocromocitoma y la correlación existente con la secreción de las mismas con el propósito de evaluar las alteraciones que podrían existir y explicar así la mayor liberación de CA por el tejido tumoral. Se estudiaron 10 feocromocitomas y 5 adrenales controles en los que se evaluó la actividad de las enzimas de síntesis: tirosina hidroxilasa (TH), aminoácido descarboxilasa (DC), dopamina ß hidroxilasa (DBH), feniletanolamina-N-metil transferasa (PNMT) y de degradación: catecol-0-metil transferasa (COMT) y monoaminooxidasa (MAO). Con respecto a TH se estudiaron además sus propiedades cinéticas así como su activación por AMP. Los resultados de actividad enzimática fueron comparadas con los valores de excreción urinaria de catecolaminas. Se encontró una mayor actividad de TH (p<0,001). DC(p<0,001) y de DBH(p<0,01) en el feocromocitoma en comparación con la médula adrenal humana normal y, en cambio, las actividades de las enzimas de degradación, MAO y COMT estaban muy disminuidas (p <0,001 y 0,01, respectivamente). Los estudios cinéticos demostraron que la TH de feocromocitoma tenía una mayor afinidad por su cofactor pteridínico reducido (20%) y una menor sensibilidad a la inhibición por producto ya que la IC de NA fue 3 veces mayor que en la adrenal control. La proporción de TH encontrada bajo la forma soluble o particulada fue similar en el tejido tumoral o en la médula adrenal, siendo también similares los niveles tisulares de sustrato tirosina (controles 21,2 + ou - 2,1microng/g; tumor 23,2 + ou - 3,4microng/g). La activación de esta enzima por dibutiril AMP cíclico tampoco se observó modificada en el tumor. Existe una estrecha correlación entre la CA secretada y la presencia de la enzima PNMT en el tumor, siendo los niveles de esta enzima en los tumores secretores de adrenalina similares a los de médula adrenal y muy bajos o indetectables en los tumores secretores de NA. Consideramos entonces que en el feocromocitoma estas alteraciones metabólicas conducirían a un nivel endógeno de CA elevado que podría liberarse sin catabolizarse por mecanismos aún no dilucidados