Multifocal pheochromocytoma-paraganglioma in a 29-year-old woman with cyanotic congenital heart disease.

BACKGROUND: Multifocal pheochromocytoma/paraganglioma presenting at an early age is commonly associated with a hereditary syndrome. CASE REPORT: A 29-year-old woman was referred for evaluation of multifocal pheochromocytoma/paraganglioma. Interestingly, her family history did not include pheochromocytoma/paraganglioma, and comprehensive genetic testing for the well-documented pheochromocytoma/paraganglioma susceptibility genes was negative. Of note, this patient had a history of a complex cardiac defect resulting in cyanotic congenital heart disease and had never undergone operative repair. Thus she lived in a chronic hypoxic state with a baseline oxygen saturation of about 80%. Laboratory evaluation found marked increases in plasma norepinephrine and normetanephrines with normal epinephrine and metanephrines. Imaging revealed 4 aortocaval masses and a right adrenal mass. After appropriate preoperative preparation she underwent successful resection of each of the neoplasms, with pathologic testing revealing multifocal pheochromocytoma/paraganglioma. DISCUSSION: This case highlights a growing recognition of the potential development of pheochromocytoma/paraganglioma in patients with cyanotic congenital heart disease. The underlying pathophysiology and phenotypic similarities between pheochromocytoma/paraganglioma in patients with cyanotic congenital heart disease and those with mutations that lead to cellular pseudohypoxia are reviewed.

Hypervascular lesions of the pancreas: Think before you act.

BACKGROUND: The "classic" CT appearance of pancreatic neuroendocrine tumors (PNETs) is a solid, hypervascular lesion; however, non-PNET diagnoses may appear similar. In addition, some PNETs have a "non-classic" appearance. METHODS: Demographic, imaging, endoscopic ultrasound-fine needle aspiration (EUS/FNA) results, and pathology data were analyzed for patients who underwent pancreatectomy for suspected or confirmed diagnosis of PNET from our institutional database. RESULTS: Forty-three patients with a hypervascular lesion on CT had pancreatectomy for a pre-operative diagnosis of PNET. Final pathology revealed PNET in 30 (70%) and non-PNET diagnoses in 13 (30%). EUS/FNA had a sensitivity of 82% for the pre-operative diagnosis of PNET in patients with "classic" CT. Of 13 non-PNET diagnoses, 7 were benign. Among a total of 41 patients with a final diagnosis of PNET, 11 (27%) had "non-classic" CT (5 hypodense solid lesions, 3 isodense solid lesions, and 3 cystic lesions). Among these patients, EUS/FNA had a sensitivity of 100% in diagnosing PNET. CONCLUSIONS: Consideration of non-PNET diagnoses is important for patients with hypervascular lesions on CT. Appropriate pre-operative evaluation will optimize treatment plans.

Thrombospondin-1 regulates the normal prostate in vivo through angiogenesis and TGF-beta activation.

Castration experiments in rodents show that the stromal vasculature is critical to the androgen-mediated prostate growth regulation. However, the role of angiogenesis inhibitors, such as thrombospondin-1 (TSP-1), in this process is unclear. TSP-1 is a multifunctional glycoprotein that can function as a potent angiogenesis inhibitor and an in vivo activator of latent transforming growth factor-beta (TGF-beta) in some tissues. On the basis of these observations, we hypothesized that TSP-1 regulated androgen withdrawal-induced prostate regression and that this process was mediated not only through antiangiogenic activity but also through TGF-beta activation. To test this, we evaluated angiogenic activity in human prostate epithelial and stromal cells treated with androgens and hypoxia in vitro. TSP-1 knockout mice were characterized to investigate the in vivo functions of TSP-1. In vitro, we found that androgens and hypoxia differentially regulated TSP-1 and angiogenic activity. Androgens stimulated normal epithelial cell, but inhibited normal stromal cell, angiogenic activity. Conversely, hypoxia stimulated stromal while inhibiting epithelial activity. Thus, in vivo, net angiogenic activity must reflect cellular interactions. And, we found that media conditioned by epithelial cells grown under normoxic conditions stimulated stromal cell angiogenic activity, and if epithelial cells were grown under hypoxic conditions, stromal activity was further increased. TSP-1 levels, however, were unchanged. In vivo, TSP-1 loss in a mouse model led to prostate epithelial hyperplasia by 3 months of age with only a modest stromal effect. Androgens suppressed TSP-1 as expression increased after castration both in normal mouse prostate and in human prostate cancer tissues. In addition, TSP-1 expression corresponded to increased TGF-beta activation in mouse tissues, specifically in the stromal compartment. These data show a critical role for TSP-1 in prostate epithelial and stromal growth regulation through angiogenic inhibition and activation of latent TGF-beta. Therefore, loss of TSP-1 during tumorigenesis would eliminate two barriers to cancer progression.