Primary malignant tumors of the adrenal glands

Malignancy must be considered in the management of adrenal lesions, including those incidentally identified on imaging studies. Adrenocortical carcinomas (ACCs) are rare tumors with an estimated annual incidence of 0.7-2 cases per year and a worldwide prevalence of 4-12 cases per million/year. However, a much higher incidence of these tumors (>15 times) has been demonstrated in south and southeastern Brazil. Most ACCs cause hypersecretion of steroids including glucocorticoids and androgens. ACC patients have a very poor prognosis with a 5-year overall survival (OS) below 30% in most series. Pheochromocytoma or paraganglioma (PPGL) is a metabolically active tumor originating from the chromaffin cells of the adrenal medulla. The incidence of PPGL is 0.2 to 0.9 cases per 100,000 individuals per year. Pheochromocytomas are present in approximately 4-7% of patients with adrenal incidentalomas. Classically, PPGL manifests as paroxysmal attacks of the following 4 symptoms: headaches, diaphoresis, palpitations, and severe hypertensive episodes. The diagnosis of malignant PPGL relies on the presence of local invasion or metastasis. In this review, we present the clinical and biochemical characteristics and pathogenesis of malignant primary lesions that affect the cortex and medulla of human adrenal glands.

PROP1 overexpression in corticotrophinomas: evidence for the role of PROP1 in the maintenance of cells committed to corticotrophic differentiation

OBJECTIVE: The expression of transcription factors involved in early pituitary development, such as PROP1 and POU1F1, has been detected in pituitary adenoma tissues. In this study, we sought to characterize the transcriptional profiles of PROP1, POU1F1, and TBX19 in functioning and nonfunctioning pituitary adenomas in an attempt to identify their roles in tumorigenesis and hormone hypersecretion. METHODS: RT-qPCR analyses were performed to assess the transcriptional pattern of PROP1, POU1F1, TBX19, and hormone-producing genes in tissue samples of corticotrophinomas (n = 10), somatotrophinomas (n = 8), and nonfunctioning adenomas (n = 6). RESULTS: Compared with normal pituitary tissue, POU1F1 was overexpressed in somatotrophinomas by 3-fold. PROP1 expression was 18-fold higher in corticotrophinomas, 10-fold higher in somatotrophinomas, and 3-fold higher in nonfunctioning adenomas. TBX19 expression was 27-fold higher in corticotrophinomas. Additionally, the level of TBX19 mRNA positively correlated with that of pro-opiomelanocortin (r = 0.49, p = 0.014). CONCLUSIONS: Our data demonstrate that PROP1 is overexpressed in pituitary adenomas, mainly in corticotrophinomas. Together with previously published data showing that patients who harbor PROP1 loss-of-function mutations present a progressive decline in corticotrope function, our results support a role for PROP1 in pituitary tumor development and in the maintenance of cell lineages committed to corticotrophic differentiation. .

Isolated familial somatotropinoma: 11Q13-LOH and gene/protein expression analysis suggests a possible involvement of aip also in non-pituitary tumorigenesis

OBJECTIVE: Non-pituitary tumors have been reported in a subset of patients harboring germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. However, no detailed investigations of non-pituitary tumors of AIP-mutated patients have been reported so far. PATIENTS: We examined a MEN1- and p53-negative mother-daughter pair with acromegaly due to somatotropinoma. Subsequently, the mother developed a large virilizing adrenocortical carcinoma and a grade II B-cell non-Hodgkin's lymphoma. DESIGN: Mutational analysis was performed by automated sequencing. Loss-of-heterozygosity (LOH) analysis was carried out by sequencing and microsatellite analysis. AIP expression was assessed through quantitative PCR (qPCR) and immunohistochemistry. RESULTS: The functional inactivating mutation c.241C>T (R81X), which blocks the AIP protein from interacting with phosphodiesterase 4A (PDE4A), was identified in the heterozygous state in the leukocyte DNA of both patients. Analyzing the tumoral DNA revealed that the AIP wild-type allele was lost in the daughter's somatotropinoma and the mother's adrenocortical carcinoma. Both tumors displayed low AIP protein expression levels. Low AIP gene expression was confirmed by qPCR in the adrenocortical carcinoma. No evidence of LOH was observed in the DNA sample from the mother's B-cell lymphoma, and this tumor displayed normal AIP immunostaining. CONCLUSIONS: Our study presents the first molecular analysis of non-pituitary tumors in AIP-mutated patients. The finding of AIP inactivation in the adrenocortical tumor suggests that further investigation of the potential role of this recently identified tumor suppressor gene in non-pituitary tumors, mainly in those tumors in which the cAMP and the 11q13 locus are implicated, is likely to be worthwhile.

Absence of PRKAR1A loss of heterozygosity in laser-captured microdissected pigmented nodular adrenocortical tissue from a patient with Carney complex caused by the novel nonsense mutation p. Y21X / Ausência da perda de heterozigose do PRKAR1A em células capturadas por microdissecção a laser de tecido de nódulo pigmentoso adrenocortical de um paciente com complexo de Carney causado por uma nova mutação nonsense

OBJECTIVE: Primary pigmented nodular adrenocortical disease (PPNAD) is the main endocrine manifestation of Carney complex, a multiple neoplasia syndrome caused by PRKAR1A gene mutations. The presence of PRKAR1A loss of heterozygosity (LOH) in adrenocortical tumorigenesis remains controversial. The aim of the present study is to investigate the presence of PRKAR1A LOH in adrenocortical cells in a patient with Carney complex. METHODS: The LOH was investigated using a PRKAR1A informative intragenic marker by GeneScan software analysis in DNA obtained from laser-captured microdissected cells of several adrenal nodules. Patients: A young adult male patient with Carney complex and his family were studied. RESULTS: A novel heterozygous mutation (p. Y21X) was identified at PRKAR1A in blood DNA of the male proband and his relatives. No PRKAR1A LOH was evidenced in the laser-captured microdissected cells from PPNAD tissue by different methodologies. CONCLUSION: We identified a new PRKAR1A nonsense mutation and in addition we did not evidence PRKAR1A LOH in laser-captured nodules cells, suggesting that adrenocortical tumorigenesis in PPNAD may occurs apart from the second hit.

OBJETIVO: A doença adrenocortical nodular pigmentosa primária (PPNAD) é uma das manifestações do complexo de Carney, uma neoplasia endócrina múltipla causada por mutações no PRKAR1A. A perda de heterozigose (LOH) do PRKAR1A na tumorigenese adrenal permanece controversa dada à possibilidade de contaminação com o tecido normal. Nosso objetivo foi investigar a presença de LOH no PRKAR1A a partir de células do nódulo adrenal de um paciente com complexo de Carney. MÉTODOS: A pesquisa da LOH do PRKAR1A foi realizada através do estudo de um marcador intragênico em DNA de células do nódulo adrenal microdissecadas a laser, evitando contaminação com o tecido normal. Pacientes: Um paciente com PPNAD e cinco familiares foram estudados. RESULTADOS: A nova mutação (p. Y21X) foi identificada no PRKAR1A sem evidência de LOH no tecido adrenal. CONCLUSÃO: Identificamos uma nova mutação no PRKAR1A e não evidenciamos LOH nas células dos nódulos adrenocorticais, sugerindo que a PPNAD possa ocorrer na ausência de um segundo evento molecular.

Síndrome de Nelson: relato de caso / Nelson's Syndrome: a case report

O objetivo deste artigo é apresentar e discutir alguns aspectos da patogênese, do diagnóstico clínico, hormonal e radiológico e do tratamento da síndrome de Nelson, com base no relato de um paciente típico portador da doença, no qual várias abordagens terapêuticas mostraram-se ineficazes.

The aim of this article is to present and discuss several aspects of the pathogenesis, the clinical, hormonal, and imaging diagnosis, and the treatment of Nelson's syndrome, based on a typical patient's report, in whom several therapeutic approaches were shown to be ineffective.

Tumores endócrinos associados às mutações das proteínas Gsalfa e Gi2alfa / Endocrine tumors associated to protein Gsalpha/Gi2alpha mutations

Diversas mutações em oncogenes promovem o crescimento tumoral através da indução de atividade de proteínas que normalmente transmitem sinais proliferativos a partir de fatores extracelulares. As proteínas G são uma família de proteínas ligadas ao nucleotídeo guanina que apresentam homologia estrutural e estão amplamente distribuídas em células eucariotas. Elas são constituídas por três sub-unidades (alfa, beta e gama). A sub-unidade alfa apresenta o sítio de ligação ao nucleotídeo guanina e é única para cada proteína G. A proteínas G estão acopladas aos receptores de superfície celular com sete hélices transmembrana com uma grande variedade de efetores intracelulares e segundos mensageiros. Um subgrupo de tumores endócrinos, incluindo os tumores hipofisários secretores de GH e ACTH, nódulos tireoideanos autônomos, tumores adrenocorticais e gonadais, foram associados a mutações somáticas ativadoras em códons altamente conservados das proteínas Gs (Arg201 e Gln227) e Gi (Arg179, Gln205). Estes achados moleculares indicaram que as proteínas G atuam como oncogenes, contribuindo no processo da tumorigênese endócrina em humanos.

Estudo clínico, molecular e terapêutico de um caso de adenoma hipofisário produtor de TSH / Clinical, molecular and therapeuthic of a case of pituitary adenoma

O adenoma produtor de TSH é o mais rato dos adenomas hipofisários (<1 por cento) e deve ser suspeitado em todo paciente com quadro clínico de hipertireoidismo e nível sangüíneo de TSH detectável, dosado por ensaios ultrassensíveis. Descrevemos a história clínica de um homem de 38 anos, tratado por hipertireoidismo com drogas antitireoideanas durante três anos, antes de se estabelecer o diagnóstico de macroadenoma hipofisário secretor de tireotrofina. Apresentava níveis elevados de T3 (380mcg/dl). T4 (18,6mcg/dl) e TSH (19,8uU/ml), este último interpretado, inicialmente, como erro laboraotrial. A TC e RNM de hipófise evidenciaram um macroadenoma com expansäo para e supra-selar. Após compensaçäo do hipertireoidismo com antitiroideanos, o paciente foi submetido à adenomectomia transesfenoidal. A análise dos exons 8 e 9 pGS e dos exons 5 e 6 da pGi em DNA extraído do tecido hipofisário, mostrou migraçäo normal no gel em gradiente de denaturaçao, afastando presença de mutaçao ativadora no gene da proteína G na etiologia do tumor. A administraçäo aguda de octreotídeo promoveu queda significativa dos níveis de TSH. Seis dias após a cirurgia, os níveis e T3, T4 e TSH estavam normais. Após dois meses, entretanto, constatou-se recorrência clínica e bioquímica do hipertireoidismo, caracterizada por níveis elevados de T3 e T4 na presença de níveis sangüíneos inapropriadamente detectáveis de TSH. Segundo nosso conhecimento bibliográfico, este foi o primeiro caso relatado no Brasil.