First report of ectopic ACTH syndrome and PTHrP-induced hypercalcemia due to a hepatoblastoma in a child.
ABSTRACT Only occasionally, endocrine-active tumors develop directly from hepatic tissue, and may lead to paraneoplastic syndromes (PNS). PNS mostly accompany malignancy of adulthood and are exceedingly rare in children.
A girl aged 6 years and 9 months presented with a 2-month history of rapidly progressive weight gain, abdominal distension, and polyuria/pollakiuria accompanied by short episodes of abdominal pain. She showed the typical clinical features of Cushing's syndrome and a huge hepatic mass. An abdominal computed tomography (CT) scan revealed a large liver tumor. Blood glucose and serum calcium were greatly elevated.
Case report describing the causative relationship of the clinical findings.
Physical examination; ultrasound of the abdomen; CT scan of the abdomen and the chest; conventional X-rays; routine hematology; blood chemistry and multiple parameters of calcium and phosphorus metabolism; multisteroid analysis in serum and urine; adrenocortical stimulation and suppression tests; histopathological assessment of the resected tumor; immunohistochemistry for ACTH, beta-endorphin, corticotrophin-releasing hormone (CRH), and PTH-related peptide (PTHrP); electron microscopy of tumor cells; ACTH and CRH extraction from the tumor tissue; and clinical follow-up for more than 20 years.
Giant hepatoblastoma (HB; approximately 1000 ml volume) of the right lobe of the liver with combined ectopic ACTH syndrome and PTHrP-induced tumor-associated hypercalcemia. Wide local excision and polychemotherapy led to complete reversal of the paraneoplastic phenotype.
This is the first report of an endocrine-active HB causing both Cushing's syndrome and PTHrP-related 'humoral hypercalcemia of malignancy'. This information should be added to the well-known beta-human chorionic gonadotropin-related paraneoplastic effects of HB in children.
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ABSTRACT: Ectopic ACTH syndrome (EAS) in youngsters has seldom been reported and is poorly known. We conducted a multicenter retrospective study involving 18 French tertiary hospitals. Cases of EAS presenting Cushing's syndrome before the age of 20 during the period from 1985 to 2008 were analyzed. Ten patients aged 14 to 20 yr were identified and compared to 20 age-matched patients with Cushing's disease diagnosed during the same period. Etiologies, clinical, biochemical and radiological features, prognosis, and treatment were described. Seven patients had well-differentiated neuroendocrine tumors (five bronchial carcinoids, one mediastinal lymph node, and one thymic), one had a poorly differentiated thymic carcinoma, one had a pleural Ewing's sarcoma, and one had a liver nested stromal epithelial tumor. At presentation, seven tumors were identified with computed tomography scanning and somatostatin receptor scintigraphy, and one with fluoro-18-L-dihydroxyphenylalanine positron emission tomography scan. Two carcinoids were occult and were identified during follow-up. Cushing's syndrome was more intense in EAS, but the clinical and biological spectrum overlapped with that of Cushing's disease. No dynamic test achieved 100% accuracy, whereas petrosal sinus sampling provided correct diagnosis in all patients tested. Medical treatment of hypercortisolism was successful in six of the eight patients with whom it was attempted, and bilateral adrenalectomy had to be performed in only two cases. Prognosis was good; nine patients with curative resection of the tumor were alive and cured (median follow-up, 6.5 yr), whereas one patient died. EAS in youngsters displays many similarities to that described in adults. The diagnostic and therapeutic algorithms recommended in adults can be used in this population.The Journal of Clinical Endocrinology and Metabolism 02/2011; 96(5):1213-22. DOI:10.1210/jc.2010-2276
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ABSTRACT: Compelling evidence broadens our understanding of tumors as highly heterogeneous populations derived from one common progenitor. In this review we portray various stages of tumorigenesis, tumor progression, self-seeding and metastasis in analogy to the superorganisms of insect societies to exemplify the highly complex architecture of a neoplasm as a system of functional "castes." Accordingly, we propose a model in which clonal expansion and cumulative acquisition of genetic alterations produce tumor compartments each equipped with distinct traits and thus distinct functions that cooperate to establish clinically apparent tumors. This functional compartment model also suggests mechanisms for the self-construction of tumor stem cell niches. Thus, thinking of a tumor as a superorganism will provide systemic insight into its functional compartmentalization and may even have clinical implications.Journal of Translational Medicine 05/2011; 9:79. DOI:10.1186/1479-5876-9-79
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ABSTRACT: Ewing tumors comprise the second most common type of bone-associated cancer in children and are characterized by oncogenic EWS/FLI1 fusion proteins and early metastasis. Compelling evidence suggests that elevated levels of intracellular oxidative stress contribute to enhanced aggressiveness of numerous cancers, possibly including Ewing tumors. Using comprehensive microarray analyses and RNA interference, we identified the six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-a membrane-bound mesenchymal stem cell marker of unknown function-as a highly expressed protein in Ewing tumors compared with benign tissues and show its regulation by EWS/FLI1. In addition, we show that STEAP1 knockdown reduces Ewing tumor proliferation, anchorage-independent colony formation as well as invasion in vitro and decreases growth and metastasis of Ewing tumor xenografts in vivo. Moreover, transcriptome and proteome analyses as well as functional studies revealed that STEAP1 expression correlates with oxidative stress responses and elevated levels of reactive oxygen species that in turn are able to regulate redox-sensitive and proinvasive genes. In synopsis, our data suggest that STEAP1 is associated with the invasive behavior and oxidative stress phenotype of Ewing tumors and point to a hitherto unanticipated oncogenic function of STEAP1.Molecular Cancer Research 11/2011; 10(1):52-65. DOI:10.1158/1541-7786.MCR-11-0524