The First International Symposium on Pheochromocytoma, held in October 2005, included discussions about developments concerning these rare catecholamine-producing tumors. Recommendations were made during the symposium for biochemical diagnosis, localization, genetics, and treatment. Measurement of plasma or urinary fractionated metanephrines, the most accurate screening approach, was recommended as the first-line test for diagnosis; reference intervals should favor sensitivity over specificity. Localization studies should only follow reasonable clinical evidence of a tumor. Preoperative pharmacologic blockade of circulatory responses to catecholamines is mandatory. Because approximately a quarter of tumors develop secondary to germ-line mutations in any one of five genes, mutation testing should be considered; however, it is not currently cost effective to test every gene in every patient. Consideration of tumor location, presence of multiple tumors, presence of metastases, and type of catecholamine produced is useful in deciding which genes to test. Inadequate methods to distinguish malignant from benign tumors and a lack of effective treatments for malignancy are important problems requiring further resolution.

Myelin inhibitors of axonal regeneration, like Nogo and MAG, block regrowth after injury to the adult CNS. While a GPI-linked receptor for Nogo (NgR) has been identified, MAG's receptor is unknown. We show that MAG inhibits regeneration by interaction with NgR. Binding of and inhibition by MAG are lost if neuronal GPI-linked proteins are cleaved. Binding of MAG to NgR-expressing cells is GPI dependent and sialic acid independent. Conversely, NgR binds to MAG-expressing cells. MAG, but not a truncated MAG that binds neurons but does not inhibit regeneration, precipitates NgR from NgR-expressing cells, DRG, and cerebellar neurons. Importantly, NgR antibody, soluble NgR, or dominant-negative NgR each prevent inhibition of neurite outgrowth by MAG. Also, MAG and Nogo66 compete for binding to NgR. These results suggest redundancy in myelin inhibitors and indicate therapies for CNS injuries.

Phaeochromocytomas (PHEO) and paragangliomas are rare catecholamine-producing tumours. Although 10-30% of these tumours metastasise, histopathological criteria to discriminate malignant from benign tumours have not been established; therefore, reliable histopathological markers predicting metastasis are urgently required. A total of 163 tumours, including 40 metastatic tumours, collected by the Phaeochromocytoma Study Group in Japan (PHEO-J) were analysed using a system called grading system for adrenal phaeochromocytoma and paraganglioma (GAPP). The tumours were scored based on GAPP criteria as follows: histological pattern, cellularity, comedo-type necrosis, capsular/ vascular invasion, Ki67 labelling index and catecholamine type. All tumours were scored from 0 to 10 points and were graded as one of the three types: well-differentiated (WD, 0-2 points), moderately differentiated (MD, 3-6 points) and poorly differentiated (PD, 7-10 points). GAPP scores of the non-metastatic and metastatic groups were 2.08G0.17 and 5.33G0.43 (meanGS.E.M., P!0.001) respectively. There was a significant negative correlation between the GAPP score and the interval until metastasis (rZK0.438, P!0.01). The mean number of years until metastasis after the initial operation was 5.5G2.6 years. The study included 111 WD, 35 MD and 17 PD types. The five-year survival of these groups was 100, 66.8 and 22.4% respectively. In addition, negative immunoreactivity for succinate dehydrogenase gene subunit B (SDHB) was observed in 13 (8%) MD or PD tumours and ten of the 13 (77%) had metastases. Our data indicate that a combination of GAPP classification and SDHB immunohistochemistry might be useful for the prediction of metastasis in these tumours.

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We investigated the immunohistochemical localization of androgen receptor (AR) using a polyclonal antibody for 55 KD recombinant human AR in human tissues fixed with 4% paraformaldehyde solution and embedded in paraffin. Immunoreactive AR was restricted to the nuclei of various tissues. Among the well-known androgen target organs, secretory cells and basal cells of the prostate, spermatogonia, spermatocytes, Sertoli cells and Leydig cells of the testis, epithelial cells of the rete testis, fibroblasts in the whole organ, squamous cells, sweat gland and hair follicle cells of the skin, and hepatocytes of the liver were positive for AR. In addition, smooth muscle cells of the prostate, uterus, urinary bladder, gastrointestinal tract, arteries, and arterioles were strongly immunoreactive for AR. Cardiac muscle and striated muscle of psoas were positive for AR. Acinar cells, ductal cells, and myoepithelial cells of the breast, endocervical and endometrial cells of the uterus, cyto- and syncytiotrophoblast of the chorionic villi, and tubules of the kidney were also positive for AR. Most FSH, LH, and some GH endocrine cells in the anterior and posterior lobes of the pituitary gland, follicular cells of the thyroid gland, and adrenocortical cells were positive for AR. Cells immunoreactive for AR were ubiquitously distributed throughout the entire body. The present study demonstrated the diversity of androgen effects on many target tissues.

Podoplanin is a specific marker for lymph vessel endothelial cells. It was noted that podoplanin is expressed in reactive mesothelial cells. The utility of podoplanin for the histological diagnosis of tumors was then investigated, especially for mesothelioma. Immunohistochemical study of podoplanin was carried out in five malignant mesotheliomas and 118 other tumors including 93 adenocarcinomas, four squamous cell carcinomas, six gastrointestinal stromal tumors and five endocrine tumors. Immunoreactivity for podoplanin was demonstrated on the cell membrane of tumor cells for all mesotheliomas. All other tumors were negative for podoplanin. Among the many antibodies used for differential diagnosis of malignant mesothelioma, podoplanin has the potential to be an excellent tumor marker in both specificity and sensitivity. The utility of podoplanin as a marker for mesothelioma will be confirmed by further studies.

The 2004 WHO classification of endocrine tumors defines pheochromocytoma as a tumor arising from chromaffin cells in the adrenal medulla. Closely related tumors in extra-adrenal sympathetic and parasympathetic paraganglia are classified as extra-adrenal paragangliomas. A pheochromocytoma is an intra-adrenal sympathetic paraganglioma. While arbitrary, this nomenclature serves to emphasize important distinctive properties of intra-adrenal tumors that must be taken into account in clinical practice and research. Those include an often adrenergic phenotype, a relatively low rate of malignancy, and a predilection to occur in particular hereditary syndromes. Current roles of pathology are limited to distinguishing primary or metastatic pheochromocytomas/paragangliomas from other endocrine or nonendocrine tumors, and flagging tumors that show features suggestive of malignant potential or syndromic disease. Future roles may involve more definitive assessment of malignancy, genotype-phenotype correlation, and identification of targets for therapy. Pathology practice currently rests mostly on interpretation of conventional histological sections stained with hematoxylin and eosin, with variable ancillary application of immunohistochemical staining. Malignancy is currently defined by the presence of metastases, not local invasion. Local invasion alone is a poor predictor of metastases, and the absence of apparent invasion does not preclude development of metastases. The two types of aggressive behavior might therefore have different biological underpinnings, and those will be resolved most effectively if consistent terminology is employed. In order to be optimally informative, pathology reports must employ consistent nomenclature and incorporate standard elements. Templates or checklists for minimal standard reporting are recommended by several pathology associations, but identification of some recommended and optional elements is currently subjective or inconsistent.

In order to characterize immunohistochemically the possible in-situ effects of gonadal steroid hormones in the human ovary during the menstrual cycle, we immunolocalized progesterone (PR), androgen (AR) and oestrogen (ER) receptors in 50 normal cycling human ovaries, and examined the relationship between these findings and the cellular localization of steroidogenic enzymes including cytochrome P-450 cholesterol side-chain cleavage (P-450scc) enzyme, 3 beta-hydroxysteroid dehydrogenase (3 beta HSD), cytochrome P-450 17 alpha-hydroxylase (P-450c17) and cytochrome P-450 aromatase (P-450arom). A large number of stromal cells were positive for AR, regardless of the distance from a follicle. No steroidogenic enzymes were observed in the stromal cells. In the pre-antral follicle, AR was observed in the theca cells. P-450scc, 3 beta HSD and P-450c17 were sporadically expressed in the theca cells in relatively large-sized pre-antral follicles. ER was positive in the granulosa cells only in the P-450arom-positive antral or pre-ovulatory follicle, which is likely to be a selected follicle. In the corpus luteum, in the period from ovulation to the mid-secretory phase, PR immunoreactivity was observed in a large number of both the luteinized granulosa and the theca cells. All steroidogenic enzymes were observed in all corpora lutea, but ER was negative in any corpus luteum. In the atretic follicle, AR was present in the theca interna cells. P-450scc, 3 beta HSD and P-450c17 were observed in the theca interna cells in some atretic follicles.(ABSTRACT TRUNCATED AT 250 WORDS)