Pheochromocytomas and extra-adrenal sympathetic paragangliomas show varied histological patterns, and it is difficult to diagnose malignancy or predict the clinical course using current histological criteria. In the present study, we reviewed 146 sympathetic paragangliomas including 116 adrenal (102 unilateral, 14 bilateral) and 30 extra-adrenal tumors including 38 metastatic tumors. We developed a scoring scale according to the following six factors: histological pattern, cellularity, coagulation necrosis, vascular/capsular invasion, Ki-67 immunoreactivity, and types of catecholamine produced. The tumors were classified as well (WD), moderately (MD), and poorly differentiated (PD) types according to their scores. The frequency of these tumor types were 113 WD (77%), 27 MD (19%), and 6 PD (4%). Metastasis was observed in 15 of 113 WD (13%), 17 of 27 MD (63%), and all 6 PD (100%). Five-year survivals of patients with metastases were 92% with WD, 69% with MD, 0% with PD. Respective 10-yr survivals were 83%, 38%, and 0%. Differences between groups were statistically significant. The data show that using this grading scoring system for sympathetic paragangliomas correlates with both metastatic potential and patient survival.
Steroidogenic acute regulatory protein (StAR) is essential for adrenal and gonadal steroidogenesis, stimulating the translocation of cholesterol to the inner mitochondrial membrane where steroidogenesis commences. StAR mutations in humans cause congenital lipoid adrenal hyperplasia (lipoid CAH), an autosomal recessive condition with severe deficiencies of all classes of steroid hormones. We previously described StAR knockout mice that mimic many features of lipoid CAH patients. By keeping StAR knockout mice alive with corticosteroid replacement, we now examine the temporal effects of StAR deficiency on the structure and function of steroidogenic tissues. The adrenal glands, affected most severely at birth, exhibited progressive increases in lipid deposits with aging. The testes of newborn StAR knockout mice contained scattered lipid deposits in the interstitial region, presumably in remnants of fetal Leydig cells. By 8 weeks of age, the interstitial lipid deposits worsened considerably and were associated with Leydig cell hyperplasia. Despite these changes, germ cells in the seminiferous tubules appeared intact histologically, suggesting that the StAR knockout mice retained some capacity for androgen biosynthesis. Sperm maturation was delayed, and the germ cells exhibited histological features of apoptosis, consistent with suboptimal androgen production. Immediately after birth, the ovaries of StAR knockout mice appeared normal. After the time of normal puberty, however, prominent lipid deposits accumulated in the interstitial region, accompanied by marked luteinization of stromal cells and incomplete follicular maturation that ultimately culminated in premature ovarian failure. These studies provide the first systematic evaluation of the developmental consequences of StAR deficiency in the various steroidogenic organs.
Cytopathologic smears and/or imprints of human adrenal cortex (9 cases) and its disorders were examined, including adrenocortical nodule (3 cases), adrenocortical adenoma (23 cases), carcinoma (8 cases), and renal cell carcinoma (6 cases). Immunocytochemistry directed against 3 beta-hydroxysteroid dehydrogenase and adrenal-4-binding protein (Ad4BP), a transcription factor in steroidogenesis, was also performed. There were no cytologic differences between normal adrenal and adrenocortical nodules. Large nuclei with prominent nucleoli were observed predominantly in adrenocortical neoplasms. Cellular atypia or pleomorphism and the degree of cohesiveness were unreliable criteria in differentiating between adrenocortical adenoma and carcinoma. Mitosis and necrotic materials were observed only in adrenocortical carcinoma. These cytologic findings were considered contributory, but not diagnostic when evaluating adrenocortical disorders because of marked intra-tumoral heterogeneity. There were no reliable cytologic criteria in differentiating adrenocortical and renal cell carcinoma. Immunocytochemistry of 3 beta-hydroxysteroid dehydrogenase and especially Ad4BP was demonstrated to aid greatly in the differential diagnosis between these carcinomas by identifying adrenocortical parenchymal cells.
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