• Role of interleukin-6 in stress response in normal and tumorous adrenal cells and during chronic inflammation.

• Signaling pathways in adrenocortical cancer.

• Calretinin and inhibin are useful in separating adrenocortical neoplasms from pheochromocytomas.

• Aberrations of centrosomes in adrenocortical tumors.

• Management of massive retroperitoneal hemorrhage from an adrenal tumor.

1
UI - 12114287
AU - Willenberg HS; Path G; Vogeli TA; Scherbaum WA; Bornstein SR
TI - Role of interleukin-6 in stress response in normal and tumorous adrenal cells and during chronic inflammation.
SO - Ann N Y Acad Sci 2002 Jun;966():304-14
AD - Department of Endocrinology at the University of Dusseldorf, Dusseldorf, Germany.
Interleukin-6 (IL-6) is the end-product of a cytokine signaling cascade and is secreted by specialized immune cells during inflammation. It has a great influence on many functions, including differentiation, stimulation, and activation of immune cells, or other cells of neuroendocrine origin. Thus, IL-6 serves as a key messenger in its communication with the neuroendocrine system, and serves as a potent activator of the hypothalamic-pituitary-adrenal axis at all levels. Changes in the levels of expression of this cytokine and its receptor have been observed during chronic inflammatory disease, and have been associated with tumorigenesis. Therefore, we studied the effect of IL-6 on normal and adenomatous human adrenal cells in vitro. The expression of IL-6 receptor mRNA was quantified within the same tissue. IL-6 potently stimulated cortisol secretion from dispersed normal human adrenal cells. We found immunoreactivity for the IL-6 receptor on cultured cells and paraffin-embedded sections of adrenal tissues. Further, there was a more pronounced expression of IL-6 mRNA in adrenal adenomas of patients with Cushing's syndrome, compared to normal human adrenals. Despite this fact, the sensitivity of cells of adenomatous adrenal glands to IL-6 was significantly decreased relative to cells from normal controls. These results were confirmed employing the permanent adrenocortical cancer cell line model NCI-H295. We infer that the loss of responsivity of tumorous adrenal cells to IL-6, and in part corticotropin, is an important step in the process of adrenal tumorigenesis by which regulation by differentiating proteins is bypassed.

2
UI - 12119279
AU - Kirschner LS
TI - Signaling pathways in adrenocortical cancer.
SO - Ann N Y Acad Sci 2002 Jun;968():222-39
AD - Unit on Genetics and Endocrinology, DEB, NICHD, National Instutes of Health, Bethesda, Maryland 20892-1862, USA.
Adrenocortical carcinoma is a rare tumor that carries a very poor prognosis. Despite efforts to develop new therapeutic regimens to treat this disease, surgery remains the mainstay of treatment. Laboratory studies of adrenocortical cancers have revealed a wide variety of signaling pathways that can be altered in these neoplasms. Although ACTH signaling through adenylyl cyclase and protein kinase A is important for normal adrenal cellular physiology, there is evidence to suggest that this pathway may inhibit the growth of adrenocortical tumors, and that inactivation of the ACTH receptor may promote tumor formation. Although multiple signal transduction pathways are essential for normal adrenal growth and hormone secretion, efforts to identify events required for neoplastic transformation have met with limited success. Alterations that have frequently been observed in adrenocortical carcinoma include up-regulation of the IGF-II system, as well as mutations in TP53 and RAS. Current studies aim to elucidate the mechanisms of tumor growth by studying proproliferative signaling pathways, such as those involving Akt/PKB and the mitogen-activated protein kinases (MAPKs). Although studies of single pathways have been helpful in guiding investigations, new tools to study the integration and multiplicity of signaling pathways hold the hope of improved understanding of the signaling pathway alterations in adrenocortical cancer.

3
UI - 11893039
AU - Jorda M; De MB; Nadji M
TI - Calretinin and inhibin are useful in separating adrenocortical neoplasms from pheochromocytomas.
SO - Appl Immunohistochem Mol Morphol 2002 Mar;10(1):67-70
AD - Department of Pathology, University of Miami/Jackson Memorial Medical Center, Florida 33136, USA. mjorda@med.miami.edu
Most adrenocortical neoplasms and pheochromocytomas can be diagnosed by a combination of clinical findings and morphologic features. Occasionally, however, this histologic differential diagnosis requires ancillary tests, such as immunohistochemistry. Both tumors are generally negative for epithelial markers but express synaptophysin. Inhibin and chromogranin are used for the diagnosis of adrenocortical neoplasms and pheochromocytomas, respectively. Both antigens, however, are expressed focally and may be completely negative, particularly in small biopsies. The authors investigated the potential value of adding calretinin to inhibin in the differential diagnosis of these tumors. Fifty-five primary adrenal neoplasms including 33 adrenocortical tumors (21 adenomas and 12 carcinomas), 22 pheochromocytomas, and 7 healthy adrenal glands were examined immunohistochemically for the expression of calretinin and inhibin. Inhibin was demonstrated in 24 (73%) adrenocortical neoplasms. When calretinin was added, the number of tumors staining positively for the two markers alone or in combination increased to 31 (94%). Both antigens showed a focal pattern of distribution in many cases. None of the pheochromocytomas reacted for any of these two markers. Healthy adrenal gland showed a distinct positive and negative pattern of immunoreactivity for both antigens in cortex and medulla, respectively. There were no differences between staining patterns of calretinin and inhibin in healthy adrenal cortex, adrenocortical adenomas, and adrenocortical carcinomas. The authors conclude that the addition of calretinin to inhibin increases the sensitivity of the diagnosis of adrenocortical neoplasms. When used together, they are highly specific and sensitive for the differential diagnosis of these tumors from pheochromocytomas. These markers, however, do not distinguish between benign and malignant adrenocortical neoplasms.

4
UI - 12011993
AU - Roshani L; Fujioka K; Auer G; Kjellman M; Lagercrantz S; Larsson C
TI - Aberrations of centrosomes in adrenocortical tumors.
SO - Int J Oncol 2002 Jun;20(6):1161-5
AD - Department of Molecular Medicine, Karolinska Hospital, CMM L8:01, SE-171 76 Stockholm, Sweden.
The frequent and generalized chromosomal imbalances that are characteristic of adrenocortical carcinomas suggest that incomplete chromosome segregation often takes place in these tumors. As a step towards elucidating the mechanism behind the multiple numerical chromosomal aberrations, we have evaluated a series of 14 such tumors for centrosome abnormalities using immunohistochemical detection of the gamma-tubulin centrosome component. The proportion of cells with more than the expected number of 2 centrosomes was moderately increased in the 4 adenomas (1-7%), while a high increase was observed in the 10 carcinomas (1-19%), as compared to the normal reference tissues (0.3%) (p<0.001). Similarly, the centrosome amplification tended to be more pronounced in the carcinomas where the aberrant cells carried 3 or 4 positive signals in 9 of the 10 tumors, and 6 signals were recorded in one tumor, while in the adenomas more than 3 signals was only recorded in one of the 4 cases. The findings demonstrate that centrosome amplifications occur frequently in both adrenocortical adenomas and carcinomas, thus supporting its role in driving the tumor development as opposed to being a consequence of it. Furthermore, the more pronounced occurrence in the malignant form as well as in the larger tumors, offers one likely explanation for the increasing generalized aneuploidy observed during the tumor development, and points to new therapeutic strategies aimed at restoring normal centrosome function.

5
UI - 11873868
AU - Hendrickson RJ; Katzman PJ; Queiroz R; Sitzmann JV; Koniaris LG
TI - Management of massive retroperitoneal hemorrhage from an adrenal tumor.
SO - Endocr J 2001 Dec;48(6):691-6
AD - Department of Surgery, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Spontaneous massive retroperitoneal hemorrhage from an adrenal gland is a rare event. A thoughtful and meticulous approach to such a patient, with appropriate diagnostic studies, ICU and surgical care are essential for patient survival. In patients with active bleeding, angiographic embolization is a valuable adjunct to achieve hemostasis, to allow for further work-up of the adrenal tumor, and an improved subsequent oncologic resection. Hemodynamically unstable patients, however, may require supportive transfusions in the intensive care unit, potential embolization if deemed feasible, or urgent surgical exploration. If possible, however, the acute surgical removal of an adrenal tumor within a large retroperitoneal hematoma should be avoided, as under such conditions a proper oncologic resection may not be possible. The possibility of a pheochromocytoma must always be entertained. Early recognition and treatment of patients with presumed adrenal insufficiency may decrease patient morbidity and mortality.

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